JEFFERSON MEDICAL COLLEGE
OF THOMAS JEFFERSON UNIVERSITY
THE DEPARTMENT OF CANCER BIOLOGY
ANNUAL REPORT
JULY 1, 2010 – JUNE 30, 2011
RICHARD G. PESTELL, M.D., Ph.D.
CHAIR
RENATO BASERGA, M.D.
VICE CHAIR – RESEARCH
MARJA NEVALAINEN, M.D., Ph.D.
VICE CHAIR – EDUCATION
ERIK KNUDSEN, Ph.D.
VICE CHAIR – ACADEMIC AFFAIRS
1
Table of Contents
Department of Cancer Biology Administration .............................................................................................4
Faculty of the Department of Cancer Biology ...............................................................................................5
Members of the Department of Cancer Biology ...........................................................................................6
Statement of Goals ..................................................................................................................................... 10
Selected Publications.................................................................................................................................. 11
Education .................................................................................................................................................... 14
Joint Seminar Series ............................................................................................................................... 15
Kimmel Cancer Center Grand Rounds .................................................................................................... 20
Faculty Reports ........................................................................................................................................... 22
Andrew E. Aplin, Ph.D............................................................................................................................. 23
Renato Baserga, M.D. ............................................................................................................................. 26
Bruno Calabretta, M.D., Ph.D. ................................................................................................................ 28
Mathew C. Casimiro, Ph.D. ..................................................................................................................... 30
Thangavel Chellappagounder, Ph.D. ...................................................................................................... 32
Clay E.S. Comstock, Ph.D. ....................................................................................................................... 33
Ayush Dagvadorj, M.D., Ph.D. ................................................................................................................ 35
Richard L. Davidson, PhD ........................................................................................................................ 36
Stephen R. Dunn ..................................................................................................................................... 37
Adam Ertel, PhD ..................................................................................................................................... 38
Paolo Fortina, MD, PhD .......................................................................................................................... 40
Maxim V. Golovkin, Ph.D. ....................................................................................................................... 43
Linda E. Greenbaum ............................................................................................................................... 44
Xuanmao Jiao, Ph.D. ............................................................................................................................... 50
Xiaoming Ju, M.D. ................................................................................................................................... 52
Karen E. Knudsen .................................................................................................................................... 57
Hilary Koprowski, M.D. ........................................................................................................................... 61
Lucia R. Languino .................................................................................................................................... 63
Zhiping Li................................................................................................................................................. 64
Jack W. London, Ph.D. ............................................................................................................................ 65
Amy K. McClendon, Ph.D. ....................................................................................................................... 66
Steven B. McMahon Ph.D. ...................................................................................................................... 67
Maria T. Nevalainen, M.D., Ph.D. ........................................................................................................... 71
Marzena J. Pedrini, Ph.D......................................................................................................................... 74
Richard G. Pestell, MB, BS, MD, PhD, FACP, FRACP ............................................................................... 75
Andrew A. Quong ................................................................................................................................... 82
Hallgeir Rui, M.D., Ph.D. ......................................................................................................................... 83
2
Federica Sotgia, PhD ............................................................................................................................... 88
Fransiscus E. Utama................................................................................................................................ 93
Kongming Wu ......................................................................................................................................... 94
Zuoren Yu ............................................................................................................................................... 96
3
Department of Cancer Biology Administration
Dr. Mark Tykocinski
Dean, Jefferson Medical College
Dr. Richard G. Pestell
Chair, Department of Cancer Biology
Dr. Marja Nevalainen
Vice Chair, Education
Dr. Renato Baserga
Vice Chair, Research
Richard Haldeman
Chief Financial Officer
Dr. Erik Knudsen
Vice Chair, Academic Affairs
Cecilia Deemer
Executive Assistant
Mary-Anne
Wallace
Executive Assistant
Atenssa L. Cheek
Administrative
Assistant
Donald Seitz
Administrative
Assistant
Dr. Richard Davidson
Director of Administration
Appointments &
Promotions Committee
Dr. Steven McMahon
Faculty Recruitment
Joan Mello
Faculty Affairs
Beth Gosnell
Administrative Assistant
Joshua Lubin
Administrator Post-Award
Dina Leibowitz
Administrative
Assistant/Timekeeper
4
Jan Rago
Pre-Award
Marian Stewart
Administrative Assistant
Faculty of the Department of Cancer Biology
Name
Mathew Casimiro
Clay Comstock
Stephen R. Dunn
Zhiping Li
Federica Sotgia
Chenguang Wang
Kongming Wu
* Wen-Shuz Yeow
Zuoren Yu
Andrew Aplin
Maxim V. Golvkin
Linda Greenbaum
D. Craig Hooper
Marja Nevalainen
Andrew Quong
Renato Baserga
Bruno Calabretta
Paolo Fortina
Erik Knudsen
Karen Knudsen
* Hilary Koprowski
Lucia R. Languino
Jack London
Steven Mc Mahon
Hallgeir Rui
Richard Pestell
Thangavel Chellappagounder
Ayush Dagvadorj
Adam Ertel
Xuanmao Jiao
Xiaoming Ju
Amy Mc Clendon
Sarmistha Mukherjee
Marzena Pedrini (Fabis)
Michael Prosniak
Sheikh Aejaz Sayeed
Lifeng Tian
* Fransiscus Utama
Marco Velasco-Velazquez
* Gang Wei
Ning Yang
* Jie Zhou
Title/Rank
Assistant Professor
Assistant Professor
Assistant Professor
Assistant Professor
Assistant Professor
Assistant Professor
Assistant Professor
Assistant Professor
Assistant Professor
Associate Professor
Associate Professor
Associate Professor
Associate Professor
Associate Professor
Associate Professor
Professor
Professor
Professor
Professor
Professor
Professor
Professor
Professor
Professor
Professor
Professor and Chairman
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
Research Instructor
* No longer at Jefferson University as of FY Ending 6/30/2011.
5
Lab/Supervisor
Pestell
K. Knudsen
Cancer Biology-Fac
Pestell
Lisanti
Cancer Biology-Fac
Pestell
E.Knudsen
Pestell
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
Cancer Biology-Fac
E. Knudsen
Nevalainen
Quong
Pestell
Pestell
E.Knudsen
Greenbaum
Hooper
Hooper
Languino
Pestell
Rui
Pestell
Pestell
Rui
Pestell
Members of the Department of Cancer Biology
STUDENTS
NAME
Michael Augello
Ethan Abel
Sucharitha Balasubramaniam
Darryll Barkhouse
Kevin Basile
Emily Bongiorno
Ryan Bourgo
Kelly Bryant
Christiane Danilo
Jeffry Dean
Chelain Goodman
Jonathan Goodwin
Ying-Hui Ko
Kevin Johnson
Kristinie Lay
Justin Lin
Stephanos Pavlides
Michael Powell
Kevin Quann
Dayana Rivadeneira
Amy Ryder
Takahiro Sato
Matthew Schiewer
Supriya Shah
Timothy Stanek
Casey Trimmer
Aubrey Watkins
LABORATORY
K. Knudsen
Aplin
K. Knudsen
Hooper
Aplin
Hooper
E. Knudsen
Lisanti
Lisanti
E. Knudsen
Rui
K. Knudsen
Sotgia
Rui
Fortina
Rui
Lisanti
Pestell
Lisanti
E. Knudsen
Rui
Rui
K. Knudsen
K. Knudsen
McMahon
Lisanti
Calabretta
NAME
POSTDOCTORAL FELLOWS
LABORATORY
Ke Chen
* Lei Chen
Hanyin Cheng
Gabriele Disanti
Anindita Dutta
Michael Gormley
Xiaofang Huang
Fred Kaplan
Pragati Katiyar
Mateusz Koptyra
Alpana Kumari
* Gaspare La Rocca
Emanuele Loro
Huimin Lu
Samanta Mariani
Hestia Mellert
* Fnu Nitin
Amy Peck (Ryder)
Dana Pintilie
Randy Schrecengost
Yongping Shao
* Ankur Sharma
* Thai Tran
Marco Trerotola
* Paraskevi Vivia Vogiatzi
Michele Weiss
Colin Wynne
Yuhua Xue
* Qiong Zhang
Zhijiu Zhong
Pestell
Rui
Pestell
Languino
Quong
Quong
Aplin
Aplin
Nevalainen
McMahon
Pestell
Languino
Calabretta
Mcmahon
Rui
Greenbaum
K. Knudsen
Aplin
Languino
Aplin
Quong
Greenbaum
Quong
* No longer at Jefferson University as of FY Ending 6/30/2011.
6
NAME
Viswandah U. Akella
Michael P. Gormley
Salmaan S. Khan
Albert Kovatich
Anita Mamtami
Hesha S. Mellert
Hui Meng
Christos Pavlides
Nicole D. Raptis
Drew Shirley
Angela Soliera
Yu Wang
VOLUNTEERS
LABORATORY
Quong
Quong
Quong
Rui
Nevalainen
Mcmahon
Pestell/Wang
Lisanti
Quong
Pestell
Calabretta
Lisanti
NAME
Elyse Amico
* Alessandra Audia
* Fatu Badiane
* David Berman
Sara Bisetto
Lisa Brown
Stephen Ciment
Neda Dadpey
Marco De Dominici
Kow Essuman
Alana Ferrari
Rebecca Galanti
Nora Homsi
* Jordan Kaplan
Kaitlyn Le
William Ostrander
Anthony Pinto
Vanessa Rose
* Roberta Toporovski
Jenny Vergalli
* Min Wang
Alicia Yanac
RESEARCH TECHNICIANS
LABORATORY
Nevalainen
Pestell
Greenbaum
K.Knudsen
Aplin
Calabretta
Greenbaum
Greenbaum
Languino
Pestell
Aplin
K.Knudsen
Rui
Pestell
Calabretta
Rui
* No longer at Jefferson University as of FY Ending 6/30/2011.
7
RESEARCH LABORATORY ASSISTANTS
Karen Markley
Marco Crosariol
Melanie Girondo
Leeanne Griffith
* Marilyn Laurelli
* Melanie Mayberry
* Alimatou Minkeu
* (Harla) Kelly Pfeiffer
* Carla Portocarrero
Christopher Reed
* Paulina Westfahl
Tiziana De Angelis
* Yuriy Smirnov
Robert Brodzik
Lei Gu
Jianwei Li
Zhiyong Liao
Greenbaum
Pestell
Rui
Languino
RESEARCH ASSOCIATES
Pestell
Nevalainen
Hooper
Nevalainen
RESEARCH LABORATORY MANAGERS
Rhonda B. Kean
Hooper
Vanessa Rose
Pestell
VISITING RESEARCH SCHOLARS
E.Knudsen
* Yang Liu
Daniela Sicoli
Baserga
* No longer at Jefferson University as of FY Ending 6/30/2011.
8
Pestell
Richard Haldeman
Chief Financial Officer
Richard Davidson
Administrative Director
* Joy Soleiman
Clinical Administrator
Atenssa L. Cheek
Mary Anne Wallace
Cecilia Deemer
Melanie Elliott
* Christina Galli
Christina Golio
Mildred Harden
ADMINISTRATION
Post Award Ops
Joshua Lubin
Karen Gosik
Tracey Kajkowski
Dina Leibowitz
Melissa McDaid
Kathy Wyszynski
ADMINISTRATIVE SUPPORT
Gillian Hewitt
Megan Jones
* Suzanne Jones
Joan Moreno (Mello)
Donald Seitz
Marian Stewart
* No longer at Jefferson University as of FY Ending 6/30/2011.
9
Pre-Award Admin
Jan Rago
Yolanda Crespo
Maureen Howard
Vida Ignatenkovas
Jacqueline Lutz
* Nicole Matthews
* Kathleen Salmon
Jeannine Voll
* Deborah Swertloff
Erin Tello
Valeriy Zheleznyak
Elizabeth Gosnell
Statement of Goals
DEPARTMENT OF CANCER BIOLOGY
JEFFERSON MEDICAL COLLEGE
“It is necessary to be involved in the action and passion of your times”
“Treat all people with dignity and respect regardless of position.”
“I am recognized for the things I do.”
The past fiscal year ending June 30, 2011 was a year that solidified our academic and financial
future. Since Dr. Pestell’s arrival in December of 2005, the department has been instrumental in
keeping the Cancer Center Support Grant (CCSG) by executing key recruitments and
strengthening scientific programs. Despite the economic constraints and the challenging
funding environment, the Cancer Biology Department has continued to grow its revenue
streams while maintaining a balanced budget.
The Department of Cancer Biology established in December 2005, was created with a mandate
to make transformational discoveries of significance for patients with cancer. Sixty new faculty
and staff moved to Thomas Jefferson University in the first wave of recruitment for the new
department of Cancer Biology. The department now has a total of 36 faculty and 91 staff
members.
The Cancer Biology Department supports the Kimmel Cancer Center facilities, which in turn
provides support for the Jefferson Medical College Research Infrastructure including: personnel
and supplies, allowing Jefferson researchers to focus on the activities of science and teaching,
and administrative staff and general services, to run the department.
HIGHLIGHTS
PUBLICATIONS
During this fiscal year the Department has published 40 papers, and a number of invited
presentations by Cancer Biology faculty members, including representations at national and
international meetings.
NEW LABORATORY EQUIPMENT
During the past year, significant equipment purchases were made in support of new faculty
recruits. Among other pieces, state-of-the-art equipment was purchased for carrying out and
analyzing the results of genomic and proteomic experiments (Biorad thermocycler, Biorad
Versadoc 5000 MP System, Fisher Scientific luminometer), for visualization of cancer cells in
culture (Nikon Ti-E inverted, phase contrast, fluorescence microscope and incubation system),
and for the transfer of genes into cancer cells (Lonza Nucleofector).
10
FUNDING
The annualized total grant support of the Cancer Biology Department for Fiscal Year 2011 was
$21,829,366. The NIH grant support for the fiscal year was $13,628,632 and the NCI grant support was
$10,445,672.
Selected Publications
since July 1, 2010
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Sato T, Neilson LM, Peck AR, Liu C, Tran TH, Witkiewicz A, Hyslop T, Nevalainen MT, Sauter G, Rui
H. Signal transducer and activator of transcription-3 and breast cancer prognosis. Am J Cancer Res.
2011;1(3):347-355.
Koptyra M, Gupta S, Talati P, Nevalainen MT. Signal transducer and activator of transcription 5a/b:
Biomarker and therapeutic target in prostate and breast cancer. Int J Biochem Cell Biol. 2011 Jun
17. [Epub ahead of print]
McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya S,
Mayhew CN, Grimes HL, Fortina P, Knudsen ES. RB and p53 Cooperate to Prevent Liver
Tumorigenesis in Response to Tissue Damage. Gastroenterology. 2011 Jun 23. [Epub ahead of
print]
Hooper DC, Roy A, Kean RB, Phares TW, Barkhouse DA. Therapeutic immune clearance of rabies
virus from the CNS. Future Virol. 2011 Mar 1;6(3):387-397.
Abel EV, Aplin AE. Finding the root of the problem: the quest to identify melanoma stem cells.
Front Biosci (Schol Ed). 2011 Jun 1;3:937-45.
Li J, Faber M, Dietzschold B, Hooper DC. The role of toll-like receptors in the induction of immune
responses during rabies virus infection. Adv Virus Res. 2011;79:115-26.
Hooper DC, Roy A, Barkhouse DA, Li J, Kean RB. Rabies virus clearance from the central nervous
system. Adv Virus Res. 2011;79:55-71.
Aplin AE, Kaplan FM, Shao Y. Mechanisms of Resistance to RAF Inhibitors in Melanoma. J Invest
Dermatol. 2011 Sep;131(9):1817-20. doi: 10.1038/jid.2011.147.Epub 2011 May 19.
DeAngelis T, Wu K, Pestell R, Baserga R. The type 1 insulin-like growth factor receptor and
resistance to DACH1. Cell Cycle. 2011 Jun 15;10(12):1956-9. Epub 2011 Jun 15.
Zhao S, Yang Y, Liu J, Liu H, Ge N, Yang H, Zhang H, Xing J. Association of mitochondrial DNA
content in peripheral blood leukocyte with hepatitis B virus-related hepatocellular carcinoma in a
Chinese Han population. Cancer Sci. 2011 Aug;102(8):1553-8. doi: 10.1111/j.13497006.2011.01968.x. Epub 2011 Jun 1.
Sussman RT, Zhang XY, McMahon SB. Enzymatic assays for assessing histone deubiquitylation
activity. Methods. 2011 Jul;54(3):339-47. Epub 2011 Apr 12.
Katiyar P, Aplin AE. FOXD3 regulates migration properties and Rnd3 expression in melanoma cells.
Mol Cancer Res. 2011 May;9(5):545-52. Epub 2011 Apr 8.
Sayeed A, Alam N, Trerotola M, Languino LR. Insulin-like growth factor 1 stimulation of androgen
receptor activity requires β(1A) integrins. J Cell Physiol. 2011 Apr 4. doi: 10.1002/jcp.22784. *Epub
ahead of print]
Bourgo RJ, Ehmer U, Sage J, Knudsen ES. RB deletion disrupts coordination between DNA
replication licensing and mitotic entry in vivo. Mol Biol Cell. 2011Apr;22(7):931-9. Epub 2011 Feb 2.
Calabretta B, Salomoni P. Inhibition of autophagy: a new strategy to enhancesensitivity of chronic
myeloid leukemia stem cells to tyrosine kinase inhibitors. Leuk Lymphoma. 2011 Feb;52 Suppl
1:54-9. Epub 2011 Jan 21. Review.
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Llaverias G, Danilo C, Mercier I, Daumer K, Capozza F, Williams TM, Sotgia F, Lisanti MP, Frank PG.
Role of cholesterol in the development and progression of breast cancer. Am J Pathol. 2011
Jan;178(1):402-12. Epub 2010 Dec 23.
Meng H, Tian L, Zhou J, Li Z, Jiao X, Li WW, Plomann M, Xu Z, Lisanti MP, Wang C, Pestell RG.
PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate
splice form cyclin D1b. Cell Cycle. 2011 Jan 1;10(1):73-81. Epub 2011 Jan 1.
Wang C, Lisanti MP, Liao DJ. Reviewing once more the c-myc and Ras collaboration: converging at
the cyclin D1-CDK4 complex and challenging basic concepts of cancer biology. Cell Cycle. 2011 Jan
1;10(1):57-67. Epub 2011 Jan 1.
Powell MJ, Casimiro MC, Cordon-Cardo C, He X, Yeow WS, Wang C, McCue PA, McBurney MW,
Pestell RG. Disruption of a Sirt1-dependent autophagy checkpoint inthe prostate results in
prostatic intraepithelial neoplasia lesion formation. Cancer Res. 2011 Feb 1;71(3):964-75. Epub
2010 Dec 28.
Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, Ojeifo J, JiaoX, Yeow WS, Katiyar S,
Shirley LA, Joyce D, Lisanti MP, Albanese C, Pestell RG. The canonical NF-kappaB pathway governs
mammary tumorigenesis in transgenic miceand tumor stem cell expansion. Cancer Res. 2010 Dec
15;70(24):10464-73.
Iozzo RV, Sanderson RD. Proteoglycans in cancer biology, tumour microenvironment and
angiogenesis. J Cell Mol Med. 2011 May;15(5):1013-31. doi: 10.1111/j.1582-4934.2010.01236.x.
Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock CE,
Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE. The retinoblastoma tumor
suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest. 2010
Dec 1;120(12):4478-92. doi: 10.1172/JCI44239. Epub 2010 Nov 22.
Weiss MB, Aplin AE. Paying "particle" attention to novel melanoma treatment strategies. J Invest
Dermatol. 2010 Dec;130(12):2699-701.
Zhou J, Liu Y, Zhang W, Popov VM, Wang M, Pattabiraman N, Suñé C, Cvekl A, Wu K, Jiang J, Wang
C, Pestell RG. Transcription elongation regulator 1 is a co-integrator of the cell fate determination
factor Dachshund homolog 1. J Biol Chem. 2010 Dec 17;285(51):40342-50. Epub 2010 Oct 18.
Johnson KJ, Peck AR, Liu C, Tran TH, Utama FE, Sjolund AB, Schaber JD, Witkiewicz AK, Rui H. PTP1B
suppresses prolactin activation of Stat5 in breast cancer cells. Am J Pathol. 2010 Dec;177(6):297183. Epub 2010 Oct 15.
Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES. RB-pathway disruption in
breast cancer: differential association with disease subtypes, disease-specific prognosis and
therapeutic response. Cell Cycle. 2010 Oct 15;9(20):4153-63. Epub 2010 Oct 27.
Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG.
Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer Res.
2010 Nov 1;70(21):8802-11. Epub 2010 Oct 12.
Wu K, Jiao X, Li Z, Katiyar S, Casimiro MC, Yang W, Zhang Q, Willmarth NE, Chepelev I, Crosariol M,
Wei Z, Hu J, Zhao K, Pestell RG. Cell fate determination factor Dachshund reprograms breast cancer
stem cell function. J Biol Chem. 2011 Jan 21;286(3):2132-42. Epub 2010 Oct 11.
Katiyar S, Casimiro MC, Dettin L, Ju X, Wagner EF, Tanaka H, Pestell RG. C-jun inhibits mammary
apoptosis in vivo. Mol Biol Cell. 2010 Dec;21(23):4264-74. Epub 2010 Oct 6.
Lidonnici MR, Audia A, Soliera AR, Prisco M, Ferrari-Amorotti G, Waldron T, Donato N, Zhang Y,
Martinez RV, Holyoake TL, Calabretta B. Expression of the transcriptional repressor Gfi-1 is
regulated by C/EBP{alpha} and is involved in its proliferation and colony formation-inhibitory
effects in p210BCR/ABL-expressing cells. Cancer Res. 2010 Oct 15;70(20):7949-59. Epub 2010 Oct
5.
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31.
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35.
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40.
Dagvadorj A, Tan SH, Liao Z, Xie J, Nurmi M, Alanen K, Rui H, Mirtti T, Nevalainen MT. N-terminal
truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate
cancer cells. Int J Biochem CellBiol. 2010 Dec;42(12):2037-46. Epub 2010 Sep 18.
Kaplan FM, Shao Y, Mayberry MM, Aplin AE. Hyperactivation of MEK-ERK1/2 signaling and
resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS
melanoma cells. Oncogene. 2011 Jan 20;30(3):366-71. Epub 2010 Sep 6.
Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, WhitakerMenezes D, Daumer KM, Lin Z, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Knudsen ES,
Sotgia F, Lisanti MP. Oxidative stress in cancer associated fibroblasts drives tumor-stroma coevolution: A new paradigm for understanding tumor metabolism, the field effect and genomic
instability in cancer cells. Cell Cycle. 2010 Aug 15;9(16):3256-76. Epub 2010 Aug 28.
Fortina P, Kricka LJ. Nanotechnology: improving clinical testing? Clin Chem.2010 Sep;56(9):1384-9.
La Rocca G, Shi B, Sepp-Lorenzino L, Baserga R. Expression of micro-RNA-145 is regulated by a
highly conserved genomic sequence 3' to the pre-miR. J Cell Physiol. 2011 Mar;226(3):602-7.
Trimmer C, Whitaker-Menezes D, Bonuccelli G, Milliman JN, Daumer KM, Aplin AE, Pestell RG,
Sotgia F, Lisanti MP, Capozza F. CAV1 inhibits metastatic potential in melanomas through
suppression of the integrin/Src/FAK signaling pathway. Cancer Res. 2010 Oct 1;70(19):7489-99.
Epub 2010 Aug 13.
Shao Y, Aplin AE. Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer
Res. 2010 Aug 15;70(16):6670-81. Epub 2010 Jul 20.
Frank PG. Endothelial caveolae and caveolin-1 as key regulators of atherosclerosis. Am J Pathol.
2010 Aug;177(2):544-6. Epub 2010 Jun 25.
DeAngelis T, Morrione A, Baserga R. Mutual interaction and reciprocal down-regulation between cmet and insulin receptor substrate-1. J Cell Physiol. 2010 Sep;224(3):658-63.
Greenbaum LE, Wells RG. The role of stem cells in liver repair and fibrosis.Int J Biochem Cell Biol.
2011 Feb;43(2):222-9. Epub 2009 Nov 13. Review.
There were 40 publications authored by Cancer Biology Members from 07/01/2010 to 06/30/2011.
13
Education
The Department of Cancer Biology supports:
 a weekly Seminar Series (Thursdays)
 Prostate Cancer Symposium
 a weekly Kimmel Cancer Center Grand
 Celebration of Life
Rounds
 Hepatoma Dinner Symposium
 Giacchinno Lecture in Cancer Research
 a weekly Research in Progress Seminar
 Sidney Weinhouse memorial lecture
(Fridays)
 a monthly KCC Translational Research
 Goto Memorial Lecture
Seminar
 Keep Your Rear in Gear 5k Walk
 Scientific and Clinical Update on Colorectal Cancer
 Life After A Cancer Diagnosis, Patient and Family Conference
There are currently 30 postdoctoral fellows and 27 students. All faculty are asked to participate
in educational support of the Medical College.
14
Joint Seminar Series
Date
Series
Speaker
Title
Friday, September 10, 2010
KCC Research In Progress Seminar
Christine Juliana
---
Friday, September 10, 2010
KCC Research In Progress Seminar
Sanda Remakus
---
Wednesday, September 22,
2010
Schwartz Center Rounds
Friday, September 24, 2010
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
KCC Research In Progress Seminar
Friday, September 24, 2010
TBD
Celestine Wanjalla
Plasma membrane microdomains,
redox
signaling
and
vascular
inflammation
---
KCC Research In Progress Seminar
Thai Tran, PhD
---
Friday, October 01, 2010
KCC Research In Progress Seminar
Joseph Comber
---
Friday, October 01, 2010
KCC Research In Progress Seminar
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
KCC Research In Progress Seminar
Dayana Rivadeneira
---
David Solit
---
Elizabeth Rogers
---
Michael Augello
---
Kerry S. Campbell, PhD
Molecular regulation of killer cell Iglike receptors (KIR) in human NK cells
Friday, October 22, 2010
KCC Research In Progress Seminar
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
KCC Research In Progress Seminar
Jordan Wesolowski
---
Friday, October 22, 2010
KCC Research In Progress Seminar
Tessa Lawrence
---
Wednesday, October 27, 2010
Xin Lin, PhD
The role of CARMA family members
in immunity and cancer
Friday, October 29, 2010
Schwartz Center Rounds
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
KCC Research In Progress Seminar
Konstantine Halkidis
---
Friday, October 29, 2010
KCC Research In Progress Seminar
Takahiro Sato
Thursday, November 04, 2010
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Robert S. Krauss, PhD
--Modeling
the
holoprosencephaly
spectrum in the mouse: Regulation of
Sonic hedgehog signaling by coreceptors
Thursday, September 23, 2010
Thursday, October 14, 2010
Friday, October 15, 2010
Friday, October 15, 2010
Thursday, October 21, 2010
Thursday, October 28, 2010
Victor Rizzo, PhD, FAHA
TBD
15
Date
Series
Speaker
Title
Thursday, November 11, 2010
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Mark Ptashne, PhD
Chromatin
architecture:
what
determines it, and does it matter?
Friday, November 12, 2010
KCC Research In Progress Seminar
Elliot Goodenough
---
Friday, November 12, 2010
KCC Research In Progress Seminar
Nicholas Sicilliano
---
Friday, November 19, 2010
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
KCC Research In Progress Seminar
Friday, November 19, 2010
KCC Research In Progress Seminar
Wednesday, November 24,
2010
Schwartz Center Rounds
TBD
Wednesday, December 22,
2010
Schwartz Center Rounds
TBD
Friday, January 07, 2011
KCC Research In Progress Seminar
Kevin Basile
---
Friday, January 07, 2011
KCC Research In Progress Seminar
Ethan Abel
---
Friday, January 14, 2011
KCC Research In Progress Seminar
Heather Montie, PhD
---
Friday, January 21, 2011
KCC Research In Progress Seminar
Zenobia Cofer
---
Friday, January 21, 2011
KCC Research In Progress Seminar
Supriya Shah
---
Wednesday, January 26, 2011
Schwartz Center Rounds
TBD
TBD
Friday, February 04, 2011
KCC Research In Progress Seminar
Changpo Chen, PhD
---
Friday, February 04, 2011
KCC Research In Progress Seminar
Yuanyuan Jin
Thursday, February 10, 2011
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Yun Qiu, PhD
Friday, February 18, 2011
KCC Research In Progress Seminar
Amy Peck, PhD
--Mechanisms of therapeutic resistance
in
prostate
cancer:
posttranscriptional and post-translational
regulation of Androgen Receptor
---
Friday, February 18, 2011
KCC Research In Progress Seminar
Darryll Barkhouse
---
Thursday, November 18, 2010
Lan Huang
Dynamic imaging of lymphocyte
activation - from single molecules to
living tissue
---
Kelly Bryant
---
Facundo D. Batista, PhD
16
Date
Wednesday, February 23,
2011
Series
Speaker
Schwartz Center Rounds
TBD
TBD
Scott D. Cramer, PhD
Use of stem cells to model prostate
cancer genetics
Friday, March 04, 2011
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
KCC Research In Progress Seminar
Friday, March 04, 2011
KCC Research In Progress Seminar
Christiane Danilo
Monday, March 07, 2011
Joint Faculty Seminar Series
Matthias Schnell, PhD
Thursday, February 24, 2011
Thursday, March 03, 2011
Title
Yihong Ye, PhD
Casey Trimmer
Protein quality control at the
endoplasmic reticulum: mechanisms
and implications for cancer therapy
----"Two birds with one stone? Bivalent
vaccines against rabies and Ebola
viruses"
Friday, March 11, 2011
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
KCC Research In Progress Seminar
Friday, March 11, 2011
KCC Research In Progress Seminar
Erin Heine
Monday, March 14, 2011
Joint Faculty Seminar Series
James Keen, PhD
Thursday, March 17, 2011
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Amy H. Bouton, PhD
Monday, March 21, 2011
Joint Faculty Seminar Series
Catherine E. Calkins, PhD
Wednesday, March 23, 2011
Schwartz Center Rounds
TBD
TBD
Thursday, March 24, 2011
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Marianne Sadar
---
Monday, March 28, 2011
Joint Faculty Seminar Series
D. Craig Hooper, PhD
"Immune mechanisms of antibody
delivery into the CNS"
Thursday, March 31, 2011
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
William C. Hahn, M.D., PhD
Functional genomics,
models and cancer
Thursday, March 10, 2011
17
Dieter Soll, PhD
The Continuing
Genetic Code
Michael Magee
-----
Evolution
of
the
"Searching for sorting mechanisms
inside cells: "Gyrating Clathrin"
Signaling complexes that regulatir of
breast tumor cell growth, motility,
and therapeutic response
Interferon-gamma, IL-17 and Chronic
Hepatitis B
experimental
Date
Series
Speaker
Title
Friday, June 03, 2011
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
KCC Research In Progress Seminar
Friday, June 03, 2011
KCC Research In Progress Seminar
Raja S. Reddy Vuyyuru, Ph.D.
---
Friday, June 17, 2011
KCC Research In Progress Seminar
Anindita Dutta, Ph.D.
---
Friday, June 17, 2011
KCC Research In Progress Seminar
Hanyin Cheng, PhD
---
Friday, April 1, 2011
KCC Research In Progress Seminar
Katherine Black
---
Friday, April 1, 2011
KCC Research In Progress Seminar
Swati Roy
---
Friday, April 15, 2011
KCC Research In Progress Seminar
Xiang Wang
---
Friday, April 29, 2011
KCC Research In Progress Seminar
Emily Gomme
---
Friday, April 29, 2011
KCC Research In Progress Seminar
Tessa Lawrence
---
Friday, April 8, 2011
KCC Research In Progress Seminar
Matthew Martz
---
Friday, April 8, 2011
KCC Research In Progress Seminar
Gregory Dickinson
---
Friday, December 10, 2010
KCC Research In Progress Seminar
Sucharitha Balasubramaniam
---
Friday, December 3, 2010
KCC Research In Progress Seminar
Jessica Gold
---
Friday, May 20, 2011
KCC Research In Progress Seminar
Pooja Talati
---
Friday, May 20, 2011
KCC Research In Progress Seminar
David Hoang
---
Friday, May 6, 2011
KCC Research In Progress Seminar
Angela Conde
Monday, April 11, 2011
Joint Faculty Seminar Series
Michael Root, PhD
Monday, April 18, 2011
Joint Faculty Seminar Series
Diane Merry, PhD
Monday, April 25, 2011
Joint Faculty Seminar Series
Jianke Zhang, PhD
Monday, April 4, 2011
Joint Faculty Seminar Series
James Jaynes, PhD
Monday, May 2, 2011
Joint Faculty Seminar Series
Erica Johnson, Ph.D.
--"How viral fusion proteins work: an
HIV-1 gp41 story"
"The role of functional domains of the
androgen receptor in its aggregation
and toxicity in the polyglutamine
expansion disease spinal and bulbar
muscular atrophy"
"FADD at the crossroads of apoptotic
and necrotic signalings"
"Defining
the
chromosomal
boundaries of epigenetic gene
regulation
"Roles for SUMO in DNA repair"
Thursday, June 02, 2011
18
Alfred Singer, M.D.
How the thymus imposes MHC
specificity on developing T cells
Shixue Shen, Ph.D
---
Date
Monday, May 9, 2011
Thursday, April 14, 2011
Thursday, April 21, 2011
Thursday, April 28, 2011
Thursday, April 7, 2011
Thursday, December 2, 2010
Thursday, December 9, 2010
Thursday, May 19, 2011
Thursday, May 26, 2011
Thursday, May 5, 2011
Wednesday, April 27, 2011
Series
Speaker
Joint Faculty Seminar Series
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Joint Seminar Series/Microbiology &
Immunology/Biochemistry/Cancer
Biology/Kimmel Cancer Center
Isidore Rigoutsos, Ph.D.
"MicroRNA
Target
Identification:
Truths and Misconceptions"
Eric Huseby, PhD
---
David B. Solit, M.D.
Genetic Predictors
dependence
Dr. Paul Monga
Zoran Culig
Schwartz Center Rounds
19
Title
of
RAF/MEK-
Beta-catenin signaling in Liver
Regeneration and HCC: Sorting the
Good from the Bad!
Different effects of supressors of
cytokine signaling in prostate cancer
depend on androgen sensitivity
Patricia Labosky, PhD
Regulation of Multipotency by this
Tanscription Factor Foxd3
Gail S. Prins, PhD
Early-life Estrogens Reprogram the
Prostate
Gland
and
Increase
Susceptibility to Adult Carcinogenesis
Pamela Geyer
Expanding transcriptional roles for a
classic Drosophila insulator protein
Patrick O'Brien, PhD
How the thymus imposes MHC
specificity on developing T cells
Mark von Zastrow, M.D., , PhD
Regulation of signaling receptors by
endocytic membrane traffic
TBD
TBD
Kimmel Cancer Center Grand Rounds
Bluemle Life Sciences Building, 233 South 10th Street, Mandeville Conference Hall, Room 101
Agenda
July 2010 to June 2011
Date
Series
Speaker
Title
Wednesday, September 15, 2010
KCC Grand Rounds
Jeffrey A. Sosman, MD
TBD
Wednesday, September 29, 2010
KCC Grand Rounds
Victor J. Strecher, PhD, MPH
TBD
Wednesday, October 13, 2010
KCC Grand Rounds
Eileen M. O'Reilly, MD
Wednesday, November 03, 2010
KCC Grand Rounds
Nancy E. Davidson, MD
Chemotherapy for Pancreatic Ductal
Adenocarcinoma: Current Status and
the Future
TBD
Wednesday, November 17, 2010
KCC Grand Rounds
Timothy R. Rebbeck, PhD
TBD
Wednesday, January 05, 2011
KCC Grand Rounds
Margaret A. Tempero, MD
Pancreatic Cancer: Reaching for a Cure
Wednesday, January 19, 2011
KCC Grand Rounds
Sergio A. Giralt, MD
Myeloma and Transplant Vision for the
Next 5 Years
Wednesday, January 26, 2011
KCC Grand Rounds
Schwartz Center Rounds
---
Wednesday, February 02, 2011
KCC Grand Rounds
Chris Logothetis, MD
TBD
Wednesday, February 09, 2011
KCC Grand Rounds
Victor J. Strecher, PhD, MPH
TBD
Wednesday, March 16, 2011
KCC Grand Rounds
Otis Brawley, MD
Opportunities for Research on
Disparities in Cancer Prevention and
Control
Wednesday, March 30, 2011
KCC Grand Rounds
William Breitbart, MD
End of Life: Balancing Hope and Reality
Wednesday, June 01, 2011
KCC Grand Rounds
David A. Scheinberg, MD, Phd
TBD
20
Date
Series
Speaker
Title
Wednesday, June 15, 2011
KCC Grand Rounds
Harold Moses
TBD
Wednesday, June 29, 2011
KCC Grand Rounds
Philip N. Tsichlis, MD
TBD
Tuesday, May 3, 2011
KCC Grand Rounds
Tony Hunter, PhD
TBD
Wednesday, April 13, 2011
KCC Grand Rounds
Jeffrey S. Miller, M.D.
The Role of NK Cells in Cancer and
Transplation
Wednesday, April 20, 2011
KCC Grand Rounds
Martine Extermann, MD, PhD
Aging and Cancer: Interactions and
Challenges
Wednesday, December 1, 2010
KCC Grand Rounds
Anthony W. Tolcher, MD, FRCP
(C)
TBD
Wednesday, May 11, 2011
KCC Grand Rounds
Anthony W. Tolcher, MD, FRCP (C)
Pharmacodynamic Studies in Phase 1
Studies - Useful Tools or an Expensive
Distraction
Wednesday, May 4, 2011
KCC Grand Rounds
H. Kim Lyerly, MD
TBD
21
Faculty Reports
22
Andrew E. Aplin, Ph.D.
Associate Professor
1.
Description of Research
Melanoma is the deadliest form of skin cancer. The
serine/threonine kinase, B-RAF, is mutated in two-thirds of
melanomas and the integrins, αvβ3 and α4β1, are overexpressed. Our goal is to determine the mechanisms by which
mutant B-RAF and aberrant integrin-matrix signaling in
melanoma cells contribute to malignant properties such as enhanced proliferation, resistance to
apoptosis, and invasion into the dermis.
2.
Current Research Projects
Mutant B-RAF signaling in melanoma
Role and regulation of FOXD3
Integrin and extracellular matrix control of melanoma progression
3.
Grant Support
NIH-R01 GM-067893 08/01/04 - 03/31/14
Adhesion and ERK signaling in melanoma
Role: Principal Investigator
The major aims of this competitive renewal are to determine roles of Rnd3 and FOXD3 in melanoma cell
invasion and whether targeting stromal fibronectin-integrin signaling, in combination with B-RAF,
inhibits melanoma cell survival.
American Cancer Society RGS #113229 01/01/08 - 12/31/11
Extracellular Matrix and Cell Signaling in Melanoma
Role: Principal Investigator
The aims of this proposal are to determine the requirement for the integrin signaling pathways and
stromal extracellular matrix in the invasive growth of melanoma cells in a skin-mimetic
microenvironment.
NIH R01 CA125103
08/01/08 - 07/31/13
B-RAF Regulation of the Cell Cycle in Melanoma
Role: Principal Investigator
The aims of this proposal are to investigate whether up-regulation of Skp2 and proteasomal degradation
of MKP3 overcome cell cycle arrest checkpoints during melanoma progression.
NIH-ARRA Supplement to GM-067893 08/01/09 - 07/31/10
Adhesion regulation of ERK nucleocytoplasmic trafficking
Role: Principal Investigator
The aims are to identify importins that control the nucleocytoplasmic trafficking of ERK, determine the
mechanism of ERK1/2 regulation of Rnd3, and determine the requirement of B-RAF activity in resistance
to anoikis in 3-D models.
NCC pre-doctoral fellowship to Rong Hu
09/01/07 - 08/31/09
Skp2 regulation of melanoma cell proliferation
23
Role: Mentor
American Cancer Society PF #113244 to R. M. Klein
01/01/08 - 12/31/09
Role of Oncogenic B-RAF in Melanoma Migration and Invasion
Role: Mentor
4.
Future Plans
Analysis of mechanisms of resistance to B-RAF inhibitors
5.
Committees
Ph.D. thesis committee:
Richard Christ (mentor, Arthur Buchberg)
Jeff Dean (mentor, Erik Knudsen)
Casey Trimmer (mentor, Michael Lisanti)
Bill Davidson (mentor, Ulrich Rodeck)
Sucharitha Balasubramaniam (mentor, Karen Knudsen)
6.
Publications
Abel EV, Aplin AE. Finding the root of the problem: the quest to identify melanoma stem cells.
Front Biosci (Schol Ed). 2011 Jun 1;3:937-45.
Aplin AE, Kaplan FM, Shao Y. Mechanisms of Resistance to RAF Inhibitors in Melanoma. J Invest
Dermatol. 2011 Sep;131(9):1817-20. doi: 10.1038/jid.2011.147. Epub 2011 May 19.
Katiyar P, Aplin AE. FOXD3 regulates migration properties and Rnd3 expression in melanoma
cells. Mol Cancer Res. 2011 May;9(5):545-52. Epub 2011 Apr 8.
Aplin AE, Sato T. Mind the BAP. Pigment Cell Melanoma Res. 2011 Feb;24(1):6-7.
Weiss MB, Aplin AE. Paying "particle" attention to novel melanoma treatment strategies. J
Invest Dermatol. 2010 Dec;130(12):2699-701.
Trimmer C, Whitaker-Menezes D, Bonuccelli G, Milliman JN, Daumer KM, Aplin AE, Pestell RG,
Sotgia F, Lisanti MP, Capozza F. CAV1 inhibits metastatic potential in melanomas through
suppression of the integrin/Src/FAK signaling pathway. Cancer Res. 2010 Oct 1;70(19):7489-99.
Epub 2010 Aug 13.
Shao Y, Aplin AE. Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells.
Cancer Res. 2010 Aug 15;70(16):6670-81. Epub 2010 Jul 20.
Matthies R, Aplin AC, Jarvis AP. Performance of a passive treatment system for net-acidic coal
mine drainage over five years of operation. Sci Total Environ. 2010 Sep 15;408(20):4877-85.
Epub 2010 Jul 6.
Kaplan FM, Mastrangelo MJ, Aplin AE. The wrath of RAFs: rogue behavior of B-RAF kinase
inhibitors. J Invest Dermatol. 2010 Nov;130(11):2669-71. Epub 2010 Jun 24.
7.
Book Chapters and Reviews
Abel, E.V. and Aplin (2010) Finding the root of the problem: the quest to identify melanoma
cells. Submitted.
Kaplan, F.M., Mastrangelo, M.J. and Aplin, A.E. (2010) The wrath of RAFs: rogue behavior of BRAF kinase inhibitors. J. Investigative Dermatol. Submitted.
8.
Presentations
Oct 2009
Department of Pharmacology, University of Illinois Chicago
24
Nov 2009
Jefferson Institute of Molecular Medicine, Departments of Dermatology and
Orthopaedic Surgery
Jan 2010
Department of Surgery, Thomas Jefferson University
March 2010
Department Of Biochemistry, University of Iowa
March 2010
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson
University
April 2010
Co-chair Introduction to Minisymposium Session ‘Signaling in Tumor Cell
Migration and Invasion’ AACR Annual Meeting, Washington D.C.
9.
Editorial Positions
Editorial advisory panel of Biochemical Journal.
10.
Teaching
Seminars in Genetics (GE720 & GE730)
Molecular Basis of Cancer (GE652)
Regulation of Cell Cycle and Apoptosis (GE636)
Protein Function and Dysfunction (BI612)
Mentor for 2 graduate students and 4 post-doctoral fellows
11.
Memberships
American Society for Cell Biology
American Association for Cancer Research
PanAmerican Society for Pigment Cell Research
Society for Matrix Biology
Society for Melanoma Research
25
Renato Baserga, M.D.
Distinguished Professor
1. Description of Research
My research has been focusing for the past 20 years on the type 1 insulin-like
growth factor receptor (IGF-IR), a growth factor receptor that plays a major role
in growth, differentiation and transformation. Antibodies to the IGF-IR are
presently in clinical trials. Many pharma companies and biotechs use reagents
(plasmids and cell lines) developed in my laboratory, which are a steady source
of income for our OTT.
2. Current Research Projects
We are presently working on 2 projects:
The role of micro RNA 145 in down-regulating the IGF-IR signaling pathway. miR145
targets and down-regulates the IGF-IR and its docking protein, the insulin receptor
substrate-1 (IRS-1) and causes a dramatic inhibition of cancer cell growth. The work
on miR145 has been done with the collaboration and support of Merck Company.
The mechanism of v-src transformation, which requires the collaboration of the IGFIR and IRS-1.
3. Grant Support
080-03800-R16719 (National Cancer Institute, NIH)
Biology of the P53 Protein
080-37038-AF0601 (Tobacco Funds)
02/01/2001 – 07/31/2010
4. Future Plans
We have isolated a clone of miR145 that produces in cells a mature, functional micro RNA. We have
found that its expression is regulated by a highly conserved sequence on 3’ side of the pre-miR. We
propose to investigate the mechanism of action of this regulatory element.
5.
Committees
Membership Committee, Kimmel Cancer Center
Executive Committee, Kimmel Cancer Center
6.
Publications
DeAngelis T, Wu K, Pestell R, Baserga R. The type 1 insulin-like growth factor receptor and
resistance to DACH1. Cell Cycle. 2011 Jun 15;10(12):1956-9. Epub 2011 Jun 15.
Baserga R. Self-plagiarism in music and science. Nature. 2011 Feb 3;470(7332):39.
La Rocca G, Shi B, Audia A, Ferrari-Amorotti G, Mellert HS, Calabretta B, McMahon SB, SeppLorenzino L, Baserga R. Regulation of microRNA-145 by growth arrest and differentiation. Exp
Cell Res. 2011 Feb 15;317(4):488-95. Epub 2010 Nov 25.
La Rocca G, Shi B, Sepp-Lorenzino L, Baserga R. Expression of micro-RNA-145 is regulated by a
highly conserved genomic sequence 3' to the pre-miR. J Cell Physiol. 2011 Mar;226(3):602-7.
DeAngelis T, Morrione A, Baserga R. Mutual interaction and reciprocal down-regulation
between c-met and insulin receptor substrate-1. J Cell Physiol. 2010 Sep;224(3):658-63.
26
7.
Book Chapters and Reviews
Baserga, R. (2009) Customizing the targeting of the IGF-1 Receptor. Future Oncology, in press
Yu, Z., Baserga, R., Chen, L., Wang, C., Lisanti, M.P. and Pestell, R.G. (in press) micro RNA, Cell
Cycle and Human Breast Cancer. Am. J. Pathology
8. Presentations
MedImmune, Osis Corporation
9. Editorial Positions
Experimental Cell Research, Journal of Cellular Physiology, American Journal of Pathology
10. Teaching
Mentoring for associates of Drs. Pestell, Sato (Ophthalmology) and Doria (Surgery)
11. Memberships
Various societies (AAAS, ACS, AAP etc.)
27
Bruno Calabretta, M.D., Ph.D.
Professor
1.
Description of Research
The primary research interest in the laboratory is the analysis of the
molecular mechanisms responsible for transformation by the BCR/ABL
oncogene of the Philadelphia chromosome. In particular, my laboratory
is investigating the apoptosis and differentiation-inhibitory effects of
BCR/ABL.
2.
Current Research Projects
A research project is assessing the role of BCR/ABL in regulating the expression/activity of transcription
factor important for normal hematopoiesis (c-Myb, C/EBPalpha, Gfi-1) using in vitro and in vivo models
of BCR/ABL-dependent transformation.
A second research project is assessing the role of tyrosine kinase inhibitors (TKI) such as the BCR/ABL
inhibitor Imatinib in inducing autophagy and how suppression of autophagy by pharmacological and
genetic inhibitors enhances TKI-induced cell death of chronic myelogenous leukemia stem cells.
3. Grant Support
NCI R01 CA095111
07/17/2002 – 06/30/2011
Transcription Factor Regulation by the BCR/ABL Oncogene
4. Future Plans
June 1, 2010: submission of R01 “Autophagy inhibition and Imatinib sensitivity of CML stem
cells”
October 1, 2010: submission of P01 “Cell Survival and Cancer”
February 2011: submission of R01 “Role of Gfi-1 in the biological effects of C/EBPalpha”
5. Committees
Ph.D. in Genetics: “Examination and Admission Committee”
KCC “Membership Committee and Flow Cytometry Committee”
6. Publications
Calabretta B, Salomoni P. Inhibition of autophagy: a new strategy to enhance sensitivity of
chronic myeloid leukemia stem cells to tyrosine kinase inhibitors. Leuk Lymphoma. 2011
Feb;52 Suppl 1:54-9. Epub 2011 Jan 21. Review.
La Rocca G, Shi B, Audia A, Ferrari-Amorotti G, Mellert HS, Calabretta B, McMahon SB, SeppLorenzino L, Baserga R. Regulation of microRNA-145 by growth arrest and differentiation. Exp
Cell Res. 2011 Feb 15;317(4):488-95. Epub 2010 Nov 25.
Lidonnici MR, Audia A, Soliera AR, Prisco M, Ferrari-Amorotti G, Waldron T, Donato N, Zhang
Y, Martinez RV, Holyoake TL, Calabretta B. Expression of the transcriptional repressor Gfi-1 is
regulated by C/EBP{alpha} and is involved in its proliferation and colony formation-inhibitory
effects in p210BCR/ABL-expressing cells. Cancer Res. 2010 Oct 15;70(20):7949-59. Epub 2010
Oct 5.
Ferrari-Amorotti G, Mariani SA, Novi C, Cattelani S, Pecorari L, Corradini F, Soliera AR,
Manzotti G, Fragliasso V, Zhang Y, Martinez RV, Lam EW, Guerzoni C, Calabretta B. The
biological effects of C/EBPalpha in K562 cells depend on the potency of the N-terminal
28
regulatory region, not on specificity of the DNA binding domain. J Biol Chem. 2010 Oct
1;285(40):30837-50. Epub 2010 Jul 20.
Tanno B, Sesti F, Cesi V, Bossi G, Ferrari-Amorotti G, Bussolari R, Tirindelli D, Calabretta B,
Raschellà G. Expression of Slug is regulated by c-Myb and is required for invasion and bone
marrow homing of cancer cells of different origin. J Biol Chem. 2010 Sep 17;285(38):2943445. Epub 2010 Jul 11.
7. Presentations
MRC Toxicology Unit, Leicester, UK, September 22, 2009: “Role of c-Myb in BCR/ABL-dependent
B-ALL”
8. Editorial Positions
Editorial Board of American Journal of Pathology and Cancer Research
9. Teaching:
First year Medical Students - Molecular Basis of disease (5 lectures)
First year Pharmacy Students - (3 lectures)
First year Ph.D. students - Core Course in “Fundamentals in Biology” (2 lectures)
Second year Ph.D. students - Course Director of “Cell Cycle and Apoptosis”
10. Memberships
American Society of Hematology
American Association for Cancer Research
29
Mathew C. Casimiro, Ph.D.
Assistant Professor
Description of Research
Cyclin D1 is a gatekeeper which controls exit from G1 state into S phase. It
partners with the cyclin dependent kinases to promote phosphorylation of
the retinoblastoma protein thus releasing the transcription factors of the
E2F family to promote DNA synthesis. The cyclin D1 gene is amplified in
approximately 30% of human breast adenocarcinomas, and the protein is
reportedly overexpressed in 60 to 80% of all cases. In mice localized
overexpression of cyclin D1 is sufficient to induce mammary tumors. We have recently described a novel
function of cyclin D1 in controlling mitochondrial function and size. Mitochondrial activity assayed by
Mitotracker staining was enhanced by genetic deletion or antisense or small interfering RNA to cyclin
D1. Global gene expression profiling and functional analysis of mammary epithelium cell-targeted cyclin
D1 antisense transgenics demonstrated that cyclin D1 inhibits mitochondrial activity and down regulates
a key component of glycolysis, namely Hexokinase II. Thus in addition to regulating nuclear DNA
synthesis, cyclin D1 also regulates mitochondrial function in vivo, coordinating metabolic substrate
utilization within the cell. The implications this novel function of cyclin D1 has on normal cellular
function and in cancer are currently being investigated.
Current Research Projects
Cyclin D1 and mitochondrial function.
ErbB2 oncogenic signaling and the role of Notch in progenitor cell maintenance.
Future plans
Future work includes defining the metabolic consequences of mis-regulated cyclin D1 expression in
breast cancer. By applying a number of biochemical assays including ATP, NAD/NADH ratio, oxygen
consumption and a metabolic profiling screen we intend to characterize the metabolic changes induced
by cyclin D1.
Publications
Velasco-Velázquez MA, Li Z, Casimiro M, Loro E, Homsi N, Pestell RG. Examining the role of cyclin
D1 in breast cancer. Future Oncol. 2011 Jun;7(6):753-65.
Bryant KG, Camacho J, Jasmin JF, Wang C, Addya S, Casimiro MC, Fortina P, Balasubramaniam S,
Knudsen KE, Schwarting R, Lisanti MP, Mercier I. Caveolin-1 overexpression enhances androgendependent growth and proliferation in the mouse prostate. Int J Biochem Cell Biol. 2011
Sep;43(9):1318-29. Epub 2011 May 12.
Powell MJ, Casimiro MC, Cordon-Cardo C, He X, Yeow WS, Wang C, McCue PA, McBurney MW,
Pestell RG. Disruption of a Sirt1-dependent autophagy checkpoint in the prostate results in
prostatic intraepithelial neoplasia lesion formation. Cancer Res. 2011 Feb 1;71(3):964-75. Epub
2010 Dec 28.
Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, Ojeifo J, Jiao X, Yeow WS,
Katiyar S, Shirley LA, Joyce D, Lisanti MP, Albanese C, Pestell RG. The canonical NF-kappaB
pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion.
Cancer Res. 2010 Dec 15;70(24):10464-73.
30
Wu K, Jiao X, Li Z, Katiyar S, Casimiro MC, Yang W, Zhang Q, Willmarth NE, Chepelev I, Crosariol
M, Wei Z, Hu J, Zhao K, Pestell RG. Cell fate determination factor Dachshund reprograms breast
cancer stem cell function. J Biol Chem. 2011 Jan 21;286(3):2132-42. Epub 2010 Oct 11.
Katiyar S, Casimiro MC, Dettin L, Ju X, Wagner EF, Tanaka H, Pestell RG. C-jun inhibits mammary
apoptosis in vivo. Mol Biol Cell. 2010 Dec;21(23):4264-74. Epub 2010 Oct 6.
Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A,
Tanowitz HB, Casimiro MC, Wang C, Pestell RG, Grieshaber P, Caro J, Sotgia F, Lisanti MP. HIF1alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor
in breast cancer cells: Autophagy drives compartment-specific oncogenesis. Cell Cycle. 2010 Sep
1;9(17):3534-51. Epub 2010 Sep 4.
Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, Frank PG,
Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP. The
autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in
fueling tumor cell metabolism. Cell Cycle. 2010 Sep 1;9(17):3485-505.
Casimiro MH, Gil MH, Leal JP. Suitability of gamma irradiated chitosan based membranes as
matrix in drug release system. Int J Pharm. 2010 Aug 16;395(1-2):142-6. Epub 2010 May 26.
Oña-Burgos P, Casimiro M, Fernández I, Navarro AV, Fernández Sánchez JF, Carretero AS,
Gutiérrez AF. Octahedral iron(II) phthalocyanine complexes: multinuclear NMR and relevance as
NO(2) chemical sensors. Dalton Trans. 2010 Jul 21;39(27):6231-8. Epub 2010 Jun 3.
Committees
PhD thesis committee member for C. Glass
31
Thangavel Chellappagounder, Ph.D.
Research Instructor
Publications
Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM,
Witkiewicz AK, Clarke R, Knudsen ES. Therapeutically activating RB:
reestablishing cell cycle control in endocrine therapy-resistant breast
cancer. Endocr Relat Cancer. 2011 Apr 28;18(3):333-45. Print 2011.
Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C,
Morrissey C, Zhang X, Comstock CE, Witkiewicz AK, Gomella L,
Knudsen ES, Nelson PS, Knudsen KE. The retinoblastoma tumor suppressor controls androgen
signaling and human prostate cancer progression. J Clin Invest. 2010 Dec 1;120(12):4478-92.
doi: 10.1172/JCI44239. Epub 2010 Nov 22.
Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in
breast cancer: key mechanisms of response and failure. Oncogene. 2010 Jul 15;29(28):4018-32.
Epub 2010 May 17.
32
Clay E.S. Comstock, Ph.D.
Assistant Professor
Description of Research & Future plans
Aberrant expression and localization of Cyclin D1 in Prostate Cancer. My
research is to understand the complex interplay between important cell
cycle regulatory factors and their contribution to prostate cancer using
cell/animal models, and human specimens. Specifically, cyclin D1 is an
important cell cycle regulatory protein that has been shown to modulate
prostate cancer cell growth through its ability to promote cell cycle
progression and to modulate the activity of the androgen receptor. Thus,
cyclin D1 is able to balance the strength and duration of the primary growth signal in prostate cancer.
Based on this, it was speculated that disruption of cyclin D1 action in prostate cancer could yield a
proliferative advantage through increased AR activity. To this end, we identified that cyclin D1 is
aberrantly regulated in the majority of human prostate cancer specimens. The consequence of
aberreanr cyclin D1 is not known, evidence suggests that loss of cyclin D1 may enhance androgen
receptor activity. My current focus is to identify the mechanisms that result in aberrant cyclin D1 in
prostate cancer. Long term, I hope to identify cell cycle specific theraputics that impact prostate cancer
progression.
Current research projects
Transcriptional regulation of the androgen receptor by cyclin D1.
Grant Support
Submitted
NIH CA139349-01A1
Mechanism: R21
Principal Investigator: Clay Comstock
DOD PC094507
Mechanism: New Investigator
Principal Investigator: Clay Comstock
Publications
Riggs T, Saini AP, Comstock CH, Lee W. Comparison of cardiac Z-score with cardiac asymmetry
for prenatal screening of congenital heart disease. Ultrasound Obstet Gynecol. 2011 Mar 11.
[Epub ahead of print]
Comstock CH. Coping with changes in health care. Am J Obstet Gynecol. 2011 Mar;204(3):256-8.
Levy DE, Byfield SD, Comstock CB, Garber JE, Syngal S, Crown WH, Shields AE. Underutilization of
BRCA1/2 testing to guide breast cancer treatment: black and Hispanic women particularly at
risk. Genet Med. 2011 Apr;13(4):349-55.
Dixit SS, Kim H, Comstock C, Faris GW. Near infrared transillumination imaging of breast cancer
with vasoactive inhalation contrast. Biomed Opt Express. 2010 Jul 27;1(1):295-309.
Comstock CH. The antenatal diagnosis of placental attachment disorders. Curr Opin Obstet
Gynecol. 2011 Apr;23(2):117-22. Review.
33
Comstock CE, Augello MA, Schiewer MJ, Karch J, Burd CJ, Ertel A, Knudsen ES, Jessen WJ,
Aronow BJ, Knudsen KE. Cyclin D1 is a selective modifier of androgen-dependent signaling and
androgen receptor function. J Biol Chem. 2011 Mar 11;286(10):8117-27. Epub 2011 Jan 5.
Comstock C. Breast magnetic resonance imaging interpretation using computer-aided detection.
Semin Roentgenol. 2011 Jan;46(1):76-85.
Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock
CE, Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE. The retinoblastoma tumor
suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest.
2010 Dec 1;120(12):4478-92. doi: 10.1172/JCI44239. Epub 2010 Nov 22.
Espinoza J, Lee W, Comstock C, Romero R, Yeo L, Rizzo G, Paladini D, Viñals F, Achiron R, Gindes
L, Abuhamad A, Sinkovskaya E, Russell E, Yagel S. Collaborative study on 4-dimensional
echocardiography for the diagnosis of fetal heart defects: the COFEHD study. J Ultrasound Med.
2010 Nov;29(11):1573-80.
Memberships
Sigma Xi
34
Ayush Dagvadorj, M.D., Ph.D.
Research Instructor
1.
Description of Research
The main focus of my research is identifying the role of Prolactin (Prl)Janus kinase 2 (Jak2)-Signal Transducer and Activator of Transcription 5
(Stat5) pathway in castration-resistant and metastatic prostate cancer
cells.
I have first-authored/co-authored papers showing that 1) Autocrine
prolactin promotes prostate cancer cell growth via Jak-2-Stat5a/b
signaling pathway, 2) Transcription factor Stat5a/b synergizes with androgen receptor in prostate cancer
cells, 3) Stat5a/b promotes growth of human prostate cancer cells in vitro and in vivo, 4) Transcription
factor Stat3 stimulates metastatic behavior of human prostate cancer cells in vivo, whereas Stat5b has a
preferential role in the promotion of prostate cancer cell viability and tumor growth, 5) developed a
new human prostate cancer cell line, CWR22Pc, which is regulated by androgens and expresses high
levels of androgen receptor and prostate specific antigen (PSA). These cells are able to form tumors in
nude mice, and when androgens are withdrawn, the tumors initially shrink and then recur as castrationresistant tumors, mimicking human prostate cancer, 6) Truncation of Stat5a/b circumvents PIAS3mediated transcriptional inhibition of Stat5 in prostate cancer cells.
2. Current Research Projects
Currently, I am working on a project identifying the molecular mechanism of androgen receptor
dependent Stat5a/b activation in prostate cancer cells, sensitization of prostate cancer cells to radiation
through Stat5a/b inhibition and genetic changes of Stat5 in prostate cancer.
3. Publications
Dagvadorj A, Tan SH, Liao Z, Xie J, Nurmi M, Alanen K, Rui H, Mirtti T, Nevalainen MT. Nterminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in
prostate cancer cells. Int J Biochem Cell Biol. 2010 Dec;42(12):2037-46. Epub 2010 Sep 18.
35
Richard L. Davidson, PhD
Research Professor
Current Academic Appointment:
Research Professor, Department of Cancer Biology, Jefferson Medical
College, Thomas Jefferson University
Future Plans: Administrator, Clinical and Translational Science Award
Committees:
Research Compliance Committee, 2003-Present
Chair, Cancer Center Membership Committee, 2005-Present
University Research Advisory Committee, 2008- Present
Steering Committee, Clinical and Translational Science Award application
Memberships: American Association for the Advancement of Science
36
Stephen R. Dunn
Assistant Professor
1.
Description of Research: provide support for research in the Core
Facility in Cancer Genomics. Research is varied and includes support work in
human clinical research and mouse models of cancer.
2.
Current Research Projects: (1) Characterization of genomic
polymorphisms, which associate with phenotypes of obesity and
hypertension in African Americans. (2) Seeking CLIA certification for complex
molecular, multi-analyte diagnostic tests in patients enrolled in clinical trial.
(3) K-Ras and BRAF genetic testing
3. Grant Support: (1) Commonwealth of PA Dept. of HEA. (2) Nucleic Acid
Facility Core Grant. (3) various sponsors
4. Future Plans: Continue to provide support in the way of robotics, DNA extraction, TAQman assays,
sequencing, OpenArray.
5. Publications:
Sharma K, Ix JH, Mathew AV, Cho M, Pflueger A, Dunn SR, Francos B, Sharma S, Falkner B, McGowan
TA, Donohue M, Ramachandrarao S, Xu R, Fervenza FC, Kopp JB. Pirfenidone for diabetic
nephropathy. J Am Soc Nephrol. 2011 Jun;22(6):1144-51. Epub 2011 Apr 21.
Pernice M, Dunn SR, Miard T, Dufour S, Dove S, Hoegh-Guldberg O. Regulation of apoptotic
mediators reveals dynamic responses to thermal stress in the reef building coral Acropora millepora.
PLoS One. 2011 Jan 24;6(1):e16095.
Hann HW, Dunn SR, Ahn M, Park SY. Question of ALT flare during switch to adefovir from
lamivudine: A single center open-label, randomized, safety study (June 17, 2005 to February 5,
2009). J Med Virol. 2010 Sep;82(9):1489-93.
Huan Y, DeLoach S, Daskalakis C, Dunn SR, Sharma K, Falkner B. Regulation of transforming growth
factor-beta1 by insulin in prediabetic African Americans. Kidney Int. 2010 Aug;78(3):318-24. Epub
2010 Apr 14.
6. Teaching: training of Renal Fellow in molecular techniques
37
Adam Ertel, PhD
Research Instructor
Current Academic Appointment
Research Instructor, Cancer Biology
Secondary Appointment
Description of Research
My research focuses on the modes of gene regulation and gene
interactions that can be inferred from large collections of mRNA
expression data. This approach is useful for identifying normal
interaction and regulatory connections between genes as well as the disruption of these connections in
complex diseases such as cancer. Bioinformatics approaches allow these connections to be easily
extended into the context of biological pathways in order to understand global chances in the presence
of disease. One particular pathway where this approach is being applied is the retinoblastoma tumor
suppressor pathway, which is disrupted in a majority of human cancers. Gene interactions in the
retinoblastoma pathway are presently being explored in the context of breast, liver, and prostate
cancer. Gene interactions revealed by large-scale mRNA expression profiles can also be used to explore
the effects of genetic variation. I am applying this approach for the combination of gene expression and
genome-wide association studies to identify how genotypic and copy number variations play a role in
the biological pathways that contribute to colorectal and other types of cancer.
Current Research Projects
1. Association between the retinoblastoma gene expression signature and clinical Outcome in
breast cancer
2. Evaluating molecular profiles for drug therapy-relevant stratification of breast cancer
3. The impact of DNA copy number variation on colorectal cancer recurrance and survival
Publications
McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya
S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES.. RB and p53 Cooperate to Prevent Liver
Tumorigenesis in Response to Tissue Damage.. Gastroenterology. 2011 Jun 24. [Epub ahead of
print]
Villa N, Bentivegna A, Ertel A, Redaelli S, Colombo C, Nacinovich R, Broggi F, Lissoni S, Bungaro S,
Addya S, Fortina P, Dalprà L.. A de novo supernumerary genomic discontinuous ring
chromosome 21 in a child with mild intellectual disability.. Am J Med Genet A. 2011
Jun;155A(6):1425-31. Epub 2011 May 13.
Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK,
Birbe RC, Howell A, Pavlides S, Gandara R, Pestell RG, Sotgia F, Philp NJ, Lisanti MP.. Evidence
for a stromal-epithelial lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in
cancer-associated fibroblasts.". Cell Cycle. 2011 Jun 1;10(11):1772-83. Epub 2011 Jun 1.
38
Witkiewicz AK, Kline J, Queenan M, Brody JR, Tsirigos A, Bilal E, Pavlides S, Ertel A, Sotgia F,
Lisanti MP.. Molecular profiling of a lethal tumor microenvironment, as defined by stromal
caveolin-1 status in breast cancers.. Cell Cycle. 2011 Jun 1;10(11):1794-809. Epub 2011 Jun 1.
Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N,
Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP.. Ketones and lactate increase cancer cell
stemness. Cell Cycle. 2011 Apr 15;10(8):1271-86.
Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N,
Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP.. Ketones and lactate increase cancer cell
stemness. Cell Cycle. 2011 Apr 15;10(8). [Epub ahead of print]
Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES..
Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant
breast cancer.. Endocr Relat Cancer. 2011 Apr 28;18(3):333-45. Print 2011.
Comstock CE, Augello MA, Schiewer MJ, Karch J, Burd CJ, Ertel A, Knudsen ES, Jessen WJ,
Aronow BJ, Knudsen KE.. Cyclin D1 is a selective modifier of androgen-dependent signaling and
androgen receptor function.. J Biol Chem. 2011 Mar 11;286(10):8117-27. Epub 2011 Jan 5.
Martinez Cantarin MP, Ertel A, Deloach S, Fortina P, Scott K, Burns TL, Falkner B.. Variants in
genes involved in functional pathways associated with hypertension in African Americans.. Clin
Transl Sci. 2010 Dec;3(6):279-86.
Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock
CE, Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE.. The retinoblastoma tumor
suppressor controls androgen signaling and human prostate cancer progression.. J Clin Invest.
2010 Dec 1;120(12):4478-92. Epub 2010 Nov 22.
Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES.. RB-pathway disruption in
breast cancer: differential association with disease subtypes, disease-specific prognosis and
therapeutic response.. Cell Cycle. 2010 Oct 15;9(20):4153-63. Epub 2010 Oct 27.
39
Paolo Fortina, MD, PhD
Professor
1.
Description of Research
As Director of the Laboratory of Cancer Genomics, I provide state-of-theart molecular assays and expertise to facilitate projects in basic,
translational and clinical research. By serving as a centralized resource
with a variety of platforms for genome-wide, gene-targeted and nextgeneration sequencing studies, the Laboratory of Cancer Genomics offers
a wide spectrum of services including nucleic acid extraction, DNA
sequence analysis, mutation detection, multiplex SNP genotyping,
genome-wide association studies, linkage analysis and copy number variation studies as well as genomewide and targeted mRNA and microRNA expression profilings. Expanded services include DNA-, RNAand microRNA-sequencing on a next-generation sequencing (NGS) platform, target-enrichment for NGS
as well as NGS ChIP-seq for chromatin occupancy and epigenetic studies associated with differentiation,
delineation of differences between normal and diseased states.
2.
Current Research Projects
GWAS in patients with agranulocytosis
GWAS in patients expressing high Hb F levels
Mapping hip dysplasia
Chromosomal targeted region enrichment using Febit Geniom Technology
Implementation of NGS-based protocols including chromatin ChIP-seq, whole transcriptome
(RNA seq), whole exon sequencing, digital mRNA expression profiling, targeted cancer gene
resequencing (DNA seq).
Implementation of SOLiD 3 Plus and 4 pipeline for high-performance computing for generated
data flow and analysis
Implementation of genome-wide mouse SNP analysis
Initiate DNA bank of TJU patients
3.
Grant Support
ACTIVE
Project Number:
Center of Excellence on Research on Obesity (P.I.: Bonita Faulkner, M.D.)
Agency:
PA Department of Public Health - $863,157
Dates:
06/01/2006 - 05/31/2010
Title:
Adipokines and Genotypes: Injury vs Protection in Obesity-Related Co-Morbidity
Role:
Co-Investigator
3 calendar
The purpose of this project is to conduct research on biomarkers that protect against obesity-related
diseases in order to advance treatments and to reduce racial disparities.
Project Number:
2 P30 CA056036-10 (P.I.: R. Pestell, M.D.)
Agency:
NIH - NCI – $238,237
Dates:
06/22/95 - 05/31/13
Title:
Translational research in cancer: Institutional Cancer Core
Role:
Director, Cancer Genomics Shared Resource
3 calendar
The major goal of this project is to provide genomic-based services to KCC investigators.
40
Project Number:
1 R01 CA132115-01A1 (P.I.: R. Pestell, M.D.)
Agency:
NIH-NCI - $207,500
Dates:
07/20/09 - 06/30/11
Title:
DACH1/Eya cell-fate determination factor and mammary tumoregenesis
Role:
Investigator
0.6 calendar
The purpose of this project is to investigate the role of DACH1 in tumors.
Project Number:
(P.I.: Bonita Faulkner, M.D.)
Agency:
NIH - $474,300
Dates:
08/17/09-07/31/14
Title:
Inflammation and Injury in Obesity Hypertension in African American Adolescents
Role:
Co-Investigator
1.2 calendar
The major goal of this project is to identify genomic polymorphisms, which associate with phenotypes of
obesity and hypertension in African Americans.
4.
Future Plans
Seeking CLIA certification for complex molecular, multi-analyte diagnostic tests in patients
enrolled in clinical trials
K-Ras and BRAF genetic testing
5.
Committees
IFCC: Steering Working Committee on Nanotechnology for Molecular Applications
6.
Publications
McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya
S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES. RB and p53 Cooperate to Prevent Liver
Tumorigenesis in Response to Tissue Damage. Gastroenterology. 2011 Jun 24. [Epub ahead of
print]
Bryant KG, Camacho J, Jasmin JF, Wang C, Addya S, Casimiro MC, Fortina P, Balasubramaniam S,
Knudsen KE, Schwarting R, Lisanti MP, Mercier I. Caveolin-1 overexpression enhances androgendependent growth and proliferation in the mouse prostate. Int J Biochem Cell Biol. 2011
Sep;43(9):1318-29. Epub 2011 May 12.
Villa N, Bentivegna A, Ertel A, Redaelli S, Colombo C, Nacinovich R, Broggi F, Lissoni S, Bungaro S,
Addya S, Fortina P, Dalprà L. A de novo supernumerary genomic discontinuous ring
chromosome 21 in a child with mild intellectual disability. Am J Med Genet A. 2011
Jun;155A(6):1425-31. Epub 2011 May 13.
Patrinos GP, Innocenti F, Cox N, Fortina P. Genetic Analysis in Translational Medicine: The 2010
GOLDEN HELIX Symposium. Hum Mutat. 2011 Jun;32(6):698-703. Epub 2011 Mar 24.
Martinez Cantarin MP, Ertel A, Deloach S, Fortina P, Scott K, Burns TL, Falkner B. Variants in
genes involved in functional pathways associated with hypertension in African Americans. Clin
Transl Sci. 2010 Dec;3(6):279-86.
Imai K, Kricka LJ, Fortina P. Concordance study of 3 direct-to-consumer genetic-testing services.
Clin Chem. 2011 Mar;57(3):518-21. Epub 2010 Dec 15.
Del Galdo F, Wermuth PJ, Addya S, Fortina P, Jimenez SA. NFκB activation and stimulation of
chemokine production in normal human macrophages by the gadolinium-based magnetic
resonance contrast agent Omniscan: possible role in the pathogenesis of nephrogenic systemic
fibrosis. Ann Rheum Dis. 2010 Nov;69(11):2024-33.
41
Kricka LJ, Imai K, Fortina P. Analytical ancestry: evolution of the array in analysis. Clin Chem.
2010 Dec;56(12):1797-803. Epub 2010 Oct 13. Review.
Fortina P, Kricka LJ.
Nanotechnology: improving clinical testing?.
Clin Chem. 2010
Sep;56(9):1384-9.
7.
Editorial Positions
1997-present
Section Editor: European Journal of Human Genetics
2000-present
Communicating Editor: Human Mutation
2007-present
Member of Editorial Board: Human Genomics and Proteomics
8.
Teaching
Training
Kristine Lay: MS degree
Matthew Smith: MS degree
Michelle Lambaugh, PhD candidate
Teaching in
GE637 - Advanced Human Genetics
GC550 - Foundations in Biomedical Sciences
Molecular and Cellular Basis of Medicine (MCBM)
Mentoring
Dr. P. Martinez (residency in Medicine) is focused on the molecular basis of hypertension and
obesity.
Dr. K. Braun (residency in Gastroenterology) is focused on the molecular basis of inflammatory
bowel disease.
Dr. F. Anni (post-doctoral fellow) is focused on modifiers of disease severity in patients with
sickle cell disease and beta thalassemia.
Ms. Gutman (Masters Program in Biotechnology) is focused on miRNA in cancer.
Dr. V. Alesi (post-doctoral fellow from the University of Rome School of Medicine) is involved in
the use of SNP-chip DNA microarrays for detecting chromosomal imbalances
9.
Memberships
American Society of Human Genetics
European Society of Human Genetics
American Association Clinical Chemistry
Association of Molecular Pathology
American Society Hematology
42
Maxim V. Golovkin, Ph.D.
Research Associate Professor
My research interests lie in the integrative area of biomedical research
that utilizes modern plant biotechnology for production of recombinant
pharmaceutical proteins. Plants have been increasingly explored as
alternative bioreactors for production of subunit vaccine components and
antibodies. The main advantages of plant expression systems are the low
cost and greater potential for scalability when compared to traditional
production systems. An additional advantage from the public’s point of
view is the greater safety, because plants themselves do not contain
mammalian pathogens and can be used directly as delivery vehicles for mucosal needle-free
immunization.
My experimental work is primarily aimed at achieving higher yields of important therapeutic agents that
display immunological activity against various diseases, including the ones considered as a threat of bioterrorism (Rabies, SARS-CoV, Smallpox, RSV, HPV, Avian Flu, Anthrax, etc). It is done using modern
constitutive and transient plant-based expression systems. Hence, all my current projects at the
Biotechnology Foundation Laboratories can be summed as:
"HIGH-YIELD PRODUCTION OF RECOMBINANT SUBUNIT VACCINE CANDIDATES IN PLANTA"
We are using plants as a vehicle to express/produce pharmaceutical agents (antigens and antibodies)
and test them to induce immune responses sufficient to protect against dangerous infections. With this
approach, we are able to produce large quantities of recombinant vaccines that can be suitable for oral
and other needle-free routes of immunization. Our scientific team is currently working to increase
production and functional/immunogenic capabilities of a variety of such vaccine candidates (see below
brief project description).
Success with this and other viral antigens that we are currently working within our laboratories makes
us believe that utilization of such plant-based scheme allows inexpensive production of many hard-toexpress and urgently needed recombinant antigens in amounts and form suitable for different routes of
immunization.
Recent Publications :
Golovkin M. Plant biotechnology for production of recombinant pharmaceuticals. Hum Vaccin.
2011 Mar;7(3):303-4.
Grokhovsky SL, Il'icheva IA, Nechipurenko DY, Golovkin MV, Panchenko LA, Polozov RV,
Nechipurenko YD. Sequence-specific ultrasonic cleavage of DNA. Biophys J. 2011 Jan
5;100(1):117-25.
43
Linda E. Greenbaum
Associate Professor
1.
Description of Research
Our laboratory focuses on elucidating the processes that coordinate
changes in physiologic and pathologic liver growth and repair.
Understanding the signaling pathways that link growth factor to cell
cycle progression and repair is not only relevant to pathophysiologic
states in which hepatocyte proliferation is insufficient, but also to
hyperproliferative states including hepatocellular carcinogenesis in which cell cycle checkpoints and
repair pathways are frequently disrupted. Identification of signaling pathways that regulate hepatic
progenitor cell self-renewal, expansion and differentiation will have wide-ranging implications for the
development of therapeutics for acute liver failure, chronic cirrhotic liver disease and hepatocellular
carcinoma.
Current Research Projects
Regulation of DNA replication in physiologic and neoplastic liver growth DNA replication is a carefully
orchestrated process essential for maintaining genomic integrity and is critical for preventing
chromosomal duplications or deletions associated with carcinogenesis. We found that the expression of
a subset of DNA replication licensing proteins are dependent on the bZIP transcription factor C/EBPβ.
We are currently investigating the mechanism responsible for C/EBPβ regulation of these DNA licensing
factors in both physiologic and neoplastic models of cell growth using genetically modified mice in which
C/EBPβ can be inducibly deleted in hepatocytes in vivo.
Mechanisms of transcriptional control in hepatocyte proliferation by microRNAs: "Fine tuning” gene
expression by small molecular weight noncoding RNA molecules including microRNAs, has been
recognized as an important mechanism regulating diverse cellular processes including development,
metabolism and cancer. Although several recent publications have identified strong correlations
between dysregulation of specific microRNAs in the livers of patients with hepatocellular carcinoma
(HCC), very little is known about the mechanism through which these microRNAs alter liver cell
proliferation and lead to the development of HCC. We are using in vivo models and computational
analyses to identify and then characterize the function of specific microRNAs that are important for
physiologic regulation of hepatocyte growth and proliferation.
Signaling pathways and the fate of hepatic progenitor cells The ability of hepatic stem cells to respond to
severe liver injury depends on a finely tuned balance of cell renewal, expansion and differentiation
which is controlled in part by the hedgehog, wnt and Notch signaling systems. Until now, lack of genetic
tools to modulate these pathways in adult hepatic progenitors has precluded the analysis of their
specific contributions to the response to liver injury. We have discovered that the forkhead transcription
factor Foxl1 uniquely marks bipotential hepatic progenitor cells and have derived both constitutive and
inducible Foxl1-Cre mouse strains to enable both gain- and loss-of-function studies in vivo through the
targeted ablation of components of these signaling pathways. Using this approach, we are currently
dissecting the signaling events that contribute to progenitor cell recruitment, differentiation and
proliferation as well as par
2. Grant Support
44
NIH R01 DK/CA56669 (PI-Greenbaum) 04/01/07-03/30/12
Transcriptional Control in Hepatocyte Proliferation
The aims of this study are to examine the transcriptional regulation of liver growth,
and metabolic homeostasis.
proliferation
NIH R01 DK-087958 (PI-Greenbaum)
04/01/10-03/0115
Signaling pathways and the fate of hepatic progenitor cells
The aims of this study are to investigate the role of Sonic Hedgehog, Wnt and Notch signaling
pathways for hepatic progenitor cell self-renewal, proliferation and differentiation
Fred and Suzanne Biesecker Family Foundation (PI-Greenbaum) 01/01/10-12/31/10
The hepatic progenitor cell niche and bile duct repair
The major objectives of the project are to investigate the role of Notch and Sonic Hedgehog
developmental signaling pathways in hepatic progenitor cells during liver repair.
3. Future Plans
Investigate the whether hepatic progenitor cells are the cell of origin in hepatocellular carcinoma
that express a “stem cell signature” and identify critical signaling pathways that regulate initiation
and progression of these tumors.
Identify the targets of microRNAs that are dysregulated in hepatocellular carcinomas for
development of novel microRNA based therapies.
4. Committees
2009-present
2010
2010
2009
2010-present
2008-present
2007-2010
Graduate Group, Biochemistry and Molecular Biology
KCC Pilot Grant Review Committee
KCC ARRA stimulus fund pilot grant review committee
NIH /NIDDK DDK-C Review Panel
NIH Review Panel: Hepatobiliary Pathophysiology Section
Vice-Chair, American Liver Foundation Grants Review Committee
Chair, AASLD abstract review committee, Experimental Hepatocellular Neoplasia
5. Publications
Sackett, S.D., Gao, Y., Shin, S., Esterson, Tsingalia, A., Hurtt, R., Brondell, K., Kaestner, K.H., and L.E.
Greenbaum. Foxl1 promotes liver repair following cholestatic injury in mice. Laboratory
Investigation, 2009, 12:1387-96.
Gao, Y., Schug, J., McKenna, L.B., Kaestner, K.H., and L.E. Greenbaum. Tissue-specific Regulation of
MicroRNA Genes. In Revision, Nucleic Acids Research.
6. Book Chapters and Reviews
Greenbaum, L. E. and R. G. Wells, The Role of Stem Cells in Liver Repair and Fibrosis, International
Journal of Biochemistry and Cell Biology, Epub, 2009 Nov 13.
7. Presentations
INVITED SEMINARS
2010
Division of Gastroenterology and Hepatology, University of Southern California
45
INVITED PRESENTATIONS
2009
Moderator, Stem Cells Workshop, American Association for the Study of Liver
Diseases Annual Meeting
2010
Invited Speaker, FASEB Summer Research Conference
8. Editorial Positions
2007- present Editorial Board, Hepatology
2007-present Consulting Editor, Journal of Clinical Investigation
2007-present Editorial Board, American Journal of Physiology
9. Teaching
2009-present
2010-present
2009
Member of Thesis Committee for Jason Correnti, TJU. Mentor: Jan Hoek.
Member of Thesis Committee for Ryan Bourgo, TJU. Mentor: Erik Knudsen.
“Stem Cells in Liver Fibrosis and Cancer, Division of Gastroenterology and
Hepatology
10. Memberships
American Association for the Study of Liver Disease
American Gastroenterological Society
International Liver Cancer Association
American Society for Biochemistry and Molecular Biology
46
D. Craig Hooper, Ph.D.
Associate Professor
1.
Description of Research
Entry of circulating cells and factors into the tissues of the central
nervous system (CNS) is regulated by the blood-brain barrier (BBB). The
central theme of the work in my laboratory is the understanding of how
innate and adaptive immune mechanisms regulate BBB function. The
maintenance of BBB integrity is important to protect sensitive CNS
tissues from immune attack, as occurs in diseases like multiple sclerosis
while functional changes in the BBB are necessary to provide immune
effectors access to infected or neoplastic brain tissues. Our studies are directed at elucidating how T
cells, B cells, and antibody enter CNS tissues and act to clear the neurotrophic rabies virus. We have
determined that an interferon-gamma-dependent process mediates therapeutic delivery of immune
effectors into CNS tissues resulting in virus clearance and are working to elucidate the precise molecular
mechanisms involved. In collaborative work we have engineered novel recombinant rabies virus
vaccines that target immune effectors to CNS tissues. These are currently under development for use in
the post-exposure treatment of rabies which remains a significant worldwide health problem with over
60,000 human deaths a year. In addition, in another collaboration we are working to provide
mechanistic support for the establishment of an immune intervention clinical trial in glioblastoma
multiforme (GBM). With a view to improving the outcome of vaccination against GBM, we are also
working define the nature of the immunoregulatory processes that protect gliomas against immune
intervention.
2.
Current Research Projects
1. Mechanisms of immune clearance of virus from the CNS.
2. Nature of antibodies capable of infiltrating CNS tissues and alterations in blood-brain barrier
function involved.
3. Regulation of blood-brain barrier integrity during CNS immunity, inflammation, and cancer.
4. Development of improved live-attenuated rabies virus vaccines for virus clearance from CNS
tissues.
5. The contribution of radical activity to neurodegenerative processes in the absence of
inflammation.
3.
Grant Support
Host-pathogen competition in IFN mediated antiviral defense. NIH/NIAID UO1 AI083046, 05/01/200904/30/2014, PI Hooper, $253,088 direct costs, 05/01/010-04/30/2011.
Passive Immunization for Neurotrophic Virus Infection. NIH/NIAID R01 AI060005, 04/01/07-03/31/10, PI
Hooper, $171,675 direct costs 04/01/09-03/31/11. No cost extension.
Vaccination against glioblastoma. Paparone, Thomas Stevens, and Yepremian Foundations,
undetermined, P.I. David Andrews, M.D., collaboration with the work of three investigators being
supported in the laboratory.
4.
Future Plans
To develop the methodology and reagents to clear viruses from the CNS tissues. Using rabies as a
model we have developed live attenuated vaccines and monoclonal antibodies capable of clearing an
otherwise lethal rabies virus infection from the CNS in mouse models. We are developing a consortium
47
with three other institutions to apply for NIH funding to provide support for translational studies to
move this work into human treatment. The lead vaccine for this work is in the process of being licensed
to a pharmaceutical firm based in India where there were over 50,000 human deaths from rabies last
year.
To exploit our findings in rabies and CNS autoimmunity to develop new modalities to deliver brain
tumor-specific immune effectors into CNS tissues bearing glioblastoma multiforme. In collaboration
with Drs. David Andrews and Larry Harshyne of the Department of Neurological Surgery we have
developed a novel vaccine that is highly effective at preventing growth of a transplantable glioma in
mice. Immunization of mice already bearing a glioma is ineffective in part due to the production of the
anti-inflammatory cytokine IL10 in the tumor. We have constructed a live-attenuated rabies virus
vaccine that may overcome the effects of IL10 and will assess this possibility.
5.
Committees
Institutional Review Board (W)
Institutional Biosafety Committee
Committee on Research
Reapplication Enhancement Award Sub-committee
Immunology and Microbial Pathogenesis PH.D. Program Core Committee
Translational Research Oversight Committee
Cancer Center Animal Colony Committee
6.
Publications
Hooper DC, Roy A, Kean RB, Phares TW, Barkhouse DA. Therapeutic immune clearance of rabies
virus from the CNS. Future Virol. 2011 Mar 1;6(3):387-397.
Li J, Faber M, Dietzschold B, Hooper DC. The role of toll-like receptors in the induction of immune
responses during rabies virus infection. Adv Virus Res. 2011;79:115-26. Review.
Hooper DC, Roy A, Barkhouse DA, Li J, Kean RB. Rabies virus clearance from the central nervous
system. Adv Virus Res. 2011;79:55-71. Review.
Vetting MW, Hegde SS, Wang M, Jacoby GA, Hooper DC, Blanchard JS. Structure of QnrB1, a
plasmid-mediated fluoroquinolone resistance factor. J Biol Chem. 2011 Jul 15;286(28):25265-73.
Epub 2011 May 19.
Truong-Bolduc QC, Bolduc GR, Okumura R, Celino B, Bevis J, Liao CH, Hooper DC. Implication of the
NorB efflux pump in the adaptation of Staphylococcus aureus to growth at acid pH and in resistance
to moxifloxacin. Antimicrob Agents Chemother. 2011 Jul;55(7):3214-9. Epub 2011 May 9.
Castegna A, Palmieri L, Spera I, Porcelli V, Palmieri F, Fabis-Pedrini MJ, Kean RB, Barkhouse DA,
Curtis MT, Hooper DC. Oxidative stress and reduced glutamine synthetase activity in the absence of
inflammation in the cortex of mice with experimental allergic encephalomyelitis. Neuroscience.
2011 Jun 30;185:97-105. Epub 2011 Apr 24.
Didier JP, Villet R, Huggler E, Lew DP, Hooper DC, Kelley WL, Vaudaux P. Impact of ciprofloxacin
exposure on Staphylococcus aureus genomic alterations linked with emergence of rifampin
resistance. Antimicrob Agents Chemother. 2011 May;55(5):1946-52. Epub 2011 Feb 28.
Kim HB, Park CH, Gavin M, Jacoby GA, Hooper DC. Cold shock induces qnrA expression in
Shewanella algae. Antimicrob Agents Chemother. 2011 Jan;55(1):414-6. Epub 2010 Nov 15.
Hyle EP, Ferraro MJ, Silver M, Lee H, Hooper DC. Ertapenem-resistant Enterobacteriaceae: risk
factors for acquisition and outcomes. Infect Control Hosp Epidemiol. 2010 Dec;31(12):1242-9. Epub
2010 Oct 28.
48
7. Book Chapters and Reviews
Hooper, D.C., Fabis, M.J., Roy, A. Free Radicals in Central Nervous System Inflammation. Oxidative Stress
and Free Radicals in Neurology, N. Gadoth, H. Hilmar (Eds.) Springer Verlag, Berlin, Heidelberg, New
York, 2010.
8. Presentations
“Active and passive immunization” Future Therapy of Human Rabies Encephalitis, Quebec
City, Quebec, Canada, October 18, 2009.
“Inhibition of rabies virus replication and spread in CNS tissues by passively administered
antibody”. Rabies in the Americas XIX, CDC, Quebec City, Quebec, Canada, October 19,
2009.
“Delivery of immune effectors across the blood-brain barrier”. KCC Joint Faculty Seminar,
TJU, November 9, 2009.
“Delivery of therapeutics across the blood-brain barrier by immune mechanisms”
Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, November 12, 2009.
“Innate and adaptive immune mechanisms in the clearance of rabies virus from the CNS”.
Immune Mechanisms of Virus Control (IMVC) Kickoff Meeting, Bethesda, Maryland,
December 1, 2009.
“Vaccination for central nervous system immunity” Jefferson Vaccine Center, TJU,
December 4, 2009.
“The production of antibody by invading B cells is required for the clearance of rabies virus
from the central nervous system”. CDC Zoonotic Disease Conference Call, January 6, 2009.
9. Editorial Positions
Editorial Board of Clinical and Developmental Immunology
10. Teaching
IMP 505 Fundamentals of Immunology – Lecturer: “T cell-mediated autoimmunity”, “Mucosal
Immunity”, “Vaccinology”.
NS 625 Neurovirology – Lecturer: “Immune activation in viral infection”, “Blood-brain barrier”, “Virus
clearance from the CNS”, “Virus-induced inflammation”.
IMP 655 Advanced Topics in Microbial Pathogenesis – Lecturer: “Borna Disease”.
MI 920 – Ph.D. Thesis Research: student Darryl Barkhouse
11. Memberships
SURE-PD Clinical Trial Steering Committee
IMVC Steering Committee
Ph.D. Committee, Rachel Knight, University of Texas Medical Branch, C.J. Peters, advisor.
NIH, NIAID Review Panels: “Protection of Human Health by Immunology and Vaccines” ZAI1-QV-I (M1 &
M2) March 1-3, 15-17, 2009.
NIH, NCCAM Special Emphasis Panels: Basic Science ZAT PK (09, 10), October 19-20, 2009, March 8-9,
2010.
49
Xuanmao Jiao, Ph.D.
Instructor
Description of Research
The protooncogene c-Jun encodes a major component of the AP-1
transcription factor and regulates diverse biological functions including
proliferation, apoptosis and migration. Several lines of evidence suggest
that c-Jun is involved in breast cancer tumorigenesis and metastasis. Our
work showed that c-Jun is necessary for cell migration and invasion. In 3T3
fibroblast, c-Jun knock out reduced cell migration and invasion through
reducing the secretion of stem cell factor (SCF). The reduction in SCF
correlated with altered c-Src expression, hyperactivating ROCK II signaling. We also demonstrated in cJun-/- cells that c-Jun regulates cellular morphogenesis, focal adhesion turnover rate, focal adhesion
number and stress fiber formation. We demonstrated that c-Jun increased in mammary epithelial cell
migration. Our preliminary data demonstrated high c-Jun expression correlated with expression of stem
cell markers. The ErbB2 transmembrane receptor is overexpressed in approximately 30% of human
tumors. Mammary gland targeted ErbB2 overexpression is sufficient for mammary tumorigenesis in
vivo. We generated FloxP-c-jun/ErbB2 double transgenic mice, and derived several stable FloxP-cjun/ErbB2 mammary tumor cell lines. FloxP-c-Jun/ErbB2/MMTV-Cre triple transgenics were generated
to excise c-Jun in the mammory glands of transenic mice. Genome wide microarray expression studies of
laser capture microdissected mammary epithelium demonstrated c-Jun expression correlated with a
stem cell expression signature in vivo. c-Jun was deleted in vivo by Cre recombinase. In the cell lines our
data showed ErbB2 increased cell motility and invasiveness and c-Jun knock out abrogated breast tumor
invasiveness. c-Jun knock out also decreased mammosphere formation in ErbB2 tumor cells. Our
mechanistic studies demonstrate c-Jun induces the production of a secreted factor that promotes
cancer stem cell expansion and cellular invasiveness. These studies will identify this secreted factor and
determine whether inactivation of this factor blocks breast cancer metastasis.
Future plans
More and more evidence showed that there is tumor stem cell and tumor stem cell played very
important role in the resistance of tumor therapy. Our future plan is to study the role of c-Jun, cyclin D1
and Dach1 in stem cell expansion and differentiation.
Current Research Projects
The role of c-Jun in Breast cancer tumor metastasis and stem cell expansion
Publications
Janowski E, Jiao X, Katiyar S, Lisanti MP, Liu M, Pestell RG, Morad M. c-Jun is required for TGF-βmediated cellular migration via nuclear Ca²╺ signaling. Int J Biochem Cell Biol. 2011
Aug;43(8):1104-13. Epub 2011 Apr 5.
Meng H, Tian L, Zhou J, Li Z, Jiao X, Li WW, Plomann M, Xu Z, Lisanti MP, Wang C, Pestell RG. PACSIN
2 represses cellular migration through direct association with cyclin D1 but not its alternate splice
form cyclin D1b. Cell Cycle. 2011 Jan 1;10(1):73-81. Epub 2011 Jan 1.
Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, Ojeifo J, Jiao X, Yeow WS, Katiyar S,
Shirley LA, Joyce D, Lisanti MP, Albanese C, Pestell RG. The canonical NF-kappaB pathway governs
mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res. 2010 Dec
15;70(24):10464-73.
50
Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG.
Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer Res.
2010 Nov 1;70(21):8802-11. Epub 2010 Oct 12.
Wu K, Jiao X, Li Z, Katiyar S, Casimiro MC, Yang W, Zhang Q, Willmarth NE, Chepelev I, Crosariol M,
Wei Z, Hu J, Zhao K, Pestell RG. Cell fate determination factor Dachshund reprograms breast cancer
stem cell function. J Biol Chem. 2011 Jan 21;286(3):2132-42. Epub 2010 Oct 11.
Committees
Bioimaging Facility Oversight Committee at Kimmel Cancer Center
Memberships
American Society of Cell Biology
51
Xiaoming Ju, M.D.
Instructor
1. Description of Research
Prostate cancer oncogenesis. I have developed new cancer cell lines
through transduction of prostate epithelial cells using oncogenic HaRas, c-Myc, v-Src and ErbB2 (NeuT). My studies are focused on the
effects of distinct oncogene on the angiogenesis, stem cell population
in prostate cancers. I am also working on the cyclinD1 & AR project,
The aim of our research is to determine new mechanisms regulating
androgen receptor (AR) function in prostate cancer cellular growth. We want to determine in vivo
significance of AR regulation by cyclin D1 / AKT1. We also try to determine functional significance of
these genes in prostate cellular growth in vivo.
Breast Cancer oncogenesis. My research is focused on the role of AKT gene plays in the proliferation,
invasion, and metastasis of breast cancer in vitro and in vivo.
2. Current Research Projects
Genetic characteristics of distinct oncogenes transformed PEC cell lines and the influence on the
angiogenesis and stem cell population.
The relationship of cyclinD1 and Androgen receptor (AR) function in prostate cancer cellular
growth.
Dose dependent AKT expression regulates invasion and metastasis of breast cancer cell.
3. Grant Support
NIH, R01 CA86072-07 (Pestell)
Androgen Receptor Function in Prostate Cancer.
(4/1/09 – 3/31/14)
$250,000/yr
4. Future Plans
Keep working on my projects, hope to get more publications in next school year and make progress in
my research and career
5. Publications
Katiyar S, Casimiro MC, Dettin L, Ju X, Wagner EF, Tanaka H, Pestell RG. C-jun inhibits mammary
apoptosis in vivo. Mol Biol Cell. 2010 Dec;21(23):4264-74. Epub 2010 Oct 6.
Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, Ojeifo J, Jiao X, Yeow WS,
Katiyar S, Shirley LA, Joyce D, Lisanti MP, Albanese C, Pestell RG. The canonical NF-kappaB
pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion.
Cancer Res. 2010 Dec 15;70(24):10464-73.
6. Memberships
American Associate of Cancer Research. Active member.
52
Erik Knudsen, Ph.D.
Professor
1.
Research Foci
Research is focused on the retinoblastoma tumor suppressor (RB). This tumor
suppressor is lost or functionally inactivated in the majority of human cancers.
The Knudsen laboratory takes a multi-disciplinary approach to understanding
how RB functions to inhibit tumorigenesis and to devise new means to
effectively target the RB-pathway in the treatment of cancer.
2.
Current and Ongoing Projects
Influence of RB on DNA replication machinery and cell cycle control:
The laboratory has identified three distinct means through which RB inhibits DNA replication and believe
that relief of this multi-fold regulation is one of the reasons why RB loss is targeted at such high
frequency in human cancers. Current investigation has revealed that other tumor suppressors can
target DNA replication control, but through mechanisms that are distinct from that of RB. In model
systems, loss of RB can either enhance proliferation or lead to genomic instability. Currently, we are
defining how RB dysfunction leads to these distinct outcomes and are modeling their relevance to
human cancers.
Role of RB in liver tumorigenesis and other environmentally-induced cancers:
Liver cancer is a major health concern. Currently, this disease is the 3rd leading cause of cancer deaths
worldwide with over 400,000 new diagnoses each year. One of the key genetic lesions found in liver
cancer is inactivation of RB. However, the role of RB loss in tumor etiology and progression remains
largely undefined. To determine the mechanism(s) by which RB prevents tumor formation in the liver, a
number of mouse model of liver specific RB deletion were interrogated. These studies revealed a novel
mechanism of RB function, indicating that RB action in this tissue is distinct from its ability to prevent
unchecked cellular proliferation. Rather, our data support the hypothesis that RB loss cooperates with
hepatic carcinogens to induce genomic instability and promote liver tumorigenesis. Liver cancer is just
one of many human cancers that has a strong environmental component. Therefore, in addition to
specific studies dissecting the action of RB loss in the liver, we have also begun to model bladder cancer,
which is induced by carcinogens from cigarettes and other toxic materials.
Action of RB in modifying response to therapy:
Given the high frequency of RB loss in human cancers we have postulated that RB-status could be an
important determinant of therapeutic outcomes. Approaches currently used to treat breast cancer
include hormonal, cytotoxic, and targeted therapeutic agents. Interestingly, diverse therapeutic agents
function through common down-stream pathways that effect cellular proliferation--particularly, they all
impinge upon the cell cycle machinery. One component of cell cycle control, which is compromised in
breast cancer at high frequency, is the RB-pathway. We have found that RB is a critical determinant of
hormonal therapies, such that RB-deficient tumors fail to effectively respond to tamoxifen. Additionally,
we have found that deregulation of the RB-pathway is associated with early relapse in breast cancer
patients treated with tamoxifen. In contrast, loss of RB enhances sensitivity to specific cytotoxic agents.
Ongoing studies are dissecting additional agents utilized in the treatment of breast cancer and other
tumor types (e.g. lung cancer), wherein RB status may be equally important in modifying therapeutic
response.
53
p16ink4a and Cyclin D1 aberrations in human cancer:
RB functions in a pathway which is controlled by the functional interplay between upstream regulators:
particularly the tumor suppressor p16ink4a and proto-oncogene cyclin D1.
Interestingly,
overproduction of cyclin D1 or loss of p16ink4a have distinct effects on cell cycle control and suggest
that intrinsic differences between components of the RB-pathway impact tumor behavior and
therapeutic response. In this context we are exploring the function of tumor associated variations in
p16ink4a and cyclin D1 (e.g. cyclin D1b) in relation to tumor development, as markers of tumor behavior
and modifiers of therapy.
3.
Grant Support:
ACTIVE:
NIH 5P30 CA056036-10 (Pestell)
$257,869 ($257,869/yr)
06/22/95 – 05/31/13
Translational Research in Cancer Senior Leadership (Deputy Director Basic Science)
NIH R01CA137494 (E Knudsen/Pestell)
Cyclin D1 variants in breast cancer
$250,000 direct/year
07/01/10 - 06/30/15
NIH R01 CA129134 (E Knudsen)
$250,000 direct/year
Action of RB Pathway in Breast Cancer Therapy
PA Tobacco Funds (E Knudsen)
$200,000 direct/year
RB pathway function
07/01/10 - 06/30/2015
NIH R01 CA127387 (E Knudsen)
$200,000 direct/year
RB tumor suppressor: action in liver tumorigenesis
01/01/08 - 12/31/12
NIH R01 CA104213 (E Knudsen)
$164,000 direct/year
BRG1/BRM: role in RB tumor suppressor signaling
06/01/04 - 05/31/10
NIH R01 CA106471 (E Knudsen)
RB mediated replication control
$164,000 direct/year
Pfizer
Therapeutic Targeting of the RB-pathway
$195,000 total
12/01/07 - 11/30/11
08/01/04 - 7/31/10
01/01/10 - 06/01/11
4.
Future Plans
To develop robust markers of RB function that can be used to inform therapeutic decisions.
To identify underlying mechanisms of RB dysfunction in breast cancer and determinants of
therapeutic response.
To determine how cyclin D1 variants function in the context of breast and liver cancer.
To define novel therapeutic interventions for the treatment of diverse cancers based on the RBpathway
5.
Publications (July 1, 2009-present):
McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya
S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES. RB and p53 Cooperate to Prevent Liver
Tumorigenesis in Response to Tissue Damage. Gastroenterology. 2011 Jun 24. [Epub ahead of
print]
54
Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N,
Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP. Ketones and lactate increase cancer cell
stemness driving recurrence, metastasis, and poor clinical outcome in breast cancer: Achieving
personalized medicine via Metabolo-Genomics. Cell Cycle. 2011 Apr 15;10(8):1271-86.
Witkiewicz AK, Knudsen ES. RB pathway and therapeutic sensitivity: new insights in breast
cancer and Tamoxifen therapy. Cell Cycle. 2011 May 15;10(10):1525. Epub 2011 May 15.
Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES.
Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant
breast cancer. Endocr Relat Cancer. 2011 Apr 28;18(3):333-45. Print 2011.
Bourgo RJ, Ehmer U, Sage J, Knudsen ES. RB deletion disrupts coordination between DNA
replication licensing and mitotic entry in vivo. Mol Biol Cell. 2011 Apr;22(7):931-9. Epub 2011
Feb 2.
Comstock CE, Augello MA, Schiewer MJ, Karch J, Burd CJ, Ertel A, Knudsen ES, Jessen WJ,
Aronow BJ, Knudsen KE. Cyclin D1 is a selective modifier of androgen-dependent signaling and
androgen receptor function. J Biol Chem. 2011 Mar 11;286(10):8117-27. Epub 2011 Jan 5.
Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock
CE, Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE. The retinoblastoma tumor
suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest.
2010 Dec 1;120(12):4478-92.
Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES. RB-pathway disruption in
breast cancer: differential association with disease subtypes, disease-specific prognosis and
therapeutic response. Cell Cycle. 2010 Oct 15;9(20):4153-63. Epub 2010 Oct 27.
Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG.
Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer Res.
2010 Nov 1;70(21):8802-11. Epub 2010 Oct 12.
Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C,
Whitaker-Menezes D, Daumer KM, Lin Z, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG,
Knudsen ES, Sotgia F, Lisanti MP. Oxidative stress in cancer associated fibroblasts drives tumorstroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and
genomic instability in cancer cells. Cell Cycle. 2010 Aug 15;9(16):3256-76. Epub 2010 Aug 28.
6.
REVIEWS AND BOOK CHAPTERS:
Knudsen, E.S. (2009). Replication factors controlling G(1): A checkpoint for pre-replication
complex assembly. Cell Cycle. 1;8(1).
McClendon, A.K., Dean, J., Knudsen, E.S. (2010). Complex role for CDK/cyclin in the control of
DNA replication licensing. In press.
7.
INVITED SEMINARS:
2007
Invited Speaker, Biomedical Sciences, Florida State University
2007
Invited Speaker, University of Southern California, Norris Cancer Center
2007
Invited Speaker, Pharmacology, University of Pittsburgh
2007
Invited Speaker, University of Alabama Birmingham, Cancer/Pathology
2008
Invited Speaker, Temple University, Fels Institute for Cancer Research
2008
Invited Speaker, University of Toronto, Molecular Medicine
2008
Invited Speaker, University of Ottawa
2008
Invited Speaker, Drexel University, Biochemistry
2009
Invited Speaker, Lankenau Institute for Medical Research
55
2009
2009
2009
2010
2010
2010
Invited Speaker, A/I Dupont Nemours, Pediatric Research Unit
Invited Speaker, University of California, Davis
Invited Speaker, New York University, Pharmacology
Invited Speaker, University of Pennsylvania, Gastroenterology
Invited Speaker, Columbia University, Department of Oncology
Invited Speaker, Mount Sinai University, Hematology Oncology
INVITED PRESENTATIONS:
2009 Invited Speaker, AACR Annual meeting
2009 Invited Speaker, Cancer Center Retreat, Michigan State University
2009 Invited Speaker, Annual Retinoblastoma Meeting
2010 Invited Speaker, Golden Helix International Genomics, Athens Greece
8. COMMITTEES:
KCC Executive Committee
KCC Education Committee
KCC Basic Science Advisory Committee
KCC Training Committee
KCC Program Advisory Committee, Chair
Thomas Jefferson University, Appointments/Promotions Committee
9.
Editorial Activities:
2005-present Editorial Board, Cancer Molecules
2008-present Editorial Board, Am. J. Pathology
2009-present Editorial Board, Genes and Cancer
2009-present Editorial Board, Mutation Research Reviews
2010-present Editorial Board, Cancer Research
56
Karen E. Knudsen
Associate Professor
Department of Cancer Biology and Department of Urology
Research Foci: Prostate cancer is the most commonly diagnosed
malignancy and second leading cause of cancer death in U.S. men. Early
prostate cancers require androgen to survive and proliferate; this
dependence is exploited in treatment for disseminated disease, wherein
androgen ablation in the first line of therapeutic
intervention. Although these regimens are initially effective, tumors
ultimately recur due to reactivation of androgen receptor (AR) signaling,
causing treatment failure and patient morbidity. Despite the importance of
understanding androgen action in the prostate, little is understood about
the mechanisms underlying androgen dependence, and the means by which the androgen requirement
is bypassed in relapsed tumors. My lab is dedicated to delineating the mechanisms that govern these
events, and in the design of new points of therapeutic intervention.
Current and Ongoing Projects:
We currently have four main projects in the lab:
1. Regulation of AR dependent gene expression and cellular proliferation by cell cycle crosstalk in
prostate cancer. Cyclin D1 is an integral component of the cell cycle machinery that is induced by
androgen in prostatic adenocarcinoma cells. However, we and others have shown that Cyclin D1 has a
second role in the regulation of androgen dependent proliferation, manifested through its ability to
modulate AR activity. We have shown that Cyclin D1 binds the AR directly and through interaction with
the N-terminus inhibits AR transactivation potential. Interaction between AR and Cyclin D1 has been
shown with endogenous proteins. The repressor function of Cyclin D1 occurs independently of its role
in the cell cycle, is dominant to the effects of known AR co-activators, and attenuates the rate of
androgen dependent proliferation. Our data put forth the hypothesis that Cyclin D1 is a critical
mediator of AR activity, that could be exploited to inhibit androgen-dependent proliferation. In this line
of investigation, we will address the mechanism of Cyclin D1 co-repressor activity and evaluate its
efficacy in vivo as an inhibitor of androgen-dependent proliferation.
2. Impact of SWI/SNF chromatin remodeling factors on AR function and prostate tumorigenesis. We and
others have shown that AR requires the action of an ATP dependent chromatin-remodeling complex,
SWI/SNF, to induce gene transcription. SWI/SNF exists in vivo as a series of biochemically diverse
complexes, and the variant composition of SWI/SNF complex is thought to underlie its specificity in
transcriptional control. We have recently determined that BAF57, a non-essential SWI/SNF subunit, is
critical for AR modulation. We show that BAF57 interacts directly with AR, is recruited to AR target
promoters in the prostate upon androgen stimulation, and is required for AR transactivation potential.
This effect of BAF57 also governs AR co-activator function, as BAF57 was required for co-activator
mediated AR enhancement and cooperated with selected co-activators to augment AR function. Lastly,
we demonstrate that abrogation of BAF57 function specifically attenuates AR dependent (but not ER
dependent) cellular proliferation. Collectively, these studies implicate BAF57 as a critical regulator of AR
and CaP proliferation, thus identifying BAF57 as a target for potential therapeutic intervention. Our data
support the hypothesis that BAF57 is a critical mediator of AR activity, acting through discrete
mechanisms to control androgen dependent proliferation. In this line of investigation, we will uncover
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the mechanisms by which BAF57 regulates AR, examine the specificity of this event under conditions
related to prostate cancer progression, and evaluate the impact of BAF57 ablation in vivo on ARdependent signaling and proliferation.
3. Impact of cell cycle deregulation on therapeutic efficacy: Our data predict that the G1-S promoting
action of AR can be manipulated to maximize the cytotoxic action of S-phase or G2/M dependent
therapeutics. This concept will be rigorously challenged herein using both in vitro and in vivo analyses.
In addition, a novel strategy will be used manipulate CDK activity for enhancing the anti-tumor action of
taxanes. Based on mechanisms of action, the proposed studies take advantage of AR-dependent cell
cycle regulation in PCa cells to reveal new strategies to effectively combat androgen dependent tumors.
Through these studies, it is our belief that novel approaches to improve disease management will be
revealed, and it is hoped that the data generated can be used to rapidly translate into a clinical trial to
improve PCa management.
4. Role of endocrine disrupting compounds (EDCs) in circumventing the androgen requirement. We
demonstrated that BPA inappropriately activates a specific subset of tumor-derived AR mutants, and
through this mechanism stimulates prostate cancer cell proliferation under conditions of androgen
depletion. The mitogenic action of BPA was sufficient in a xenograft model of prostate cancer to shorten
the time to recurrence and enhance tumor growth after therapeutic intervention. These data were the
first to examine the impact of endocrine-disrupting compounds (EDCs) on prostate cancer management,
revealed the focal point of BPA activity, and have important clinical implications. In a recent
comprehensive screen, we determined that multiple EDCs impinge on specific AR mutants to facilitate
cellular proliferation. Combined, these findings support the hypothesis that specific environmental
agents can contribute to therapeutic bypass in prostate cancer, and that EDC action is facilitated through
secondary events known to occur during tumor progression. This section of the lab will to determine the
mechanism, specificity, and consequence of EDC activity in prostate cancer:
Grant Support:
R01 CA116777
(PI Karen E. Knudsen)
06/01/06-07/31/11
“Role of BAF57 in AR control and prostate cancer growth”: The goal of this project is to examine the
mechanisms by which BAF57 induces AR function and regulates AR-dependent proliferation.
R01 ES016675-06
(PI Karen E. Knudsen)
04/01/02-08/31/12
“Endocrine Disruption and Prostate Cancer Therapy”: The goal of this project is to determine the
mechanisms by which xenoestrogens influence androgen receptor function and prostate cancer therapy.
R01 CA099996
(PI: Karen Knudsen)
06/01/09-05/31/2014
Cyclin D1: Mechanism and consequence of AR inhibition”: The goal of this project is to examine cross
talk between the androgen receptor and the cell cycle machinery, with a specific emphasis on cyclin
D1a. The specific aims were designed to delineate the mechanism and specificity of cyclin D1a activity
on hormone function.
Prostate Cancer Foundation Creativity Award (joint PIs: Adam Dicker & Karen Knudsen) 03/01/0903/01/10
58
Self-seeding and radiation therapy: a new strategy against metastatic prostate cancer. This award will
test the novel hypothesis that survival of widespread metastases are dependent on the local tumor
environment.
Future Plans:
To develop metrics of therapeutic response in prostate cancer.
To identify new points of therapeutic intervention through interrogation of the androgen
receptor pathway
To determine the impact of cell cycle control on prostate cancer progression.
Publications:
Bryant KG, Camacho J, Jasmin JF, Wang C, Addya S, Casimiro MC, Fortina P, Balasubramaniam S,
Knudsen KE, Schwarting R, Lisanti MP, Mercier I. Caveolin-1 overexpression enhances
androgen-dependent growth and proliferation in the mouse prostate. Int J Biochem Cell Biol.
2011 Sep;43(9):1318-29. Epub 2011 May 12.
Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES.
Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant
breast cancer. Endocr Relat Cancer. 2011 Apr 28;18(3):333-45. Print 2011.
Olsen A, Christensen J, Knudsen KE, Johnsen NF, Overvad K, Tjønneland A. Prediagnostic plasma
enterolactone levels and mortality among women with breast cancer. Breast Cancer Res Treat.
2011 Aug;128(3):883-9. Epub 2011 Feb 22.
Knudsen KE. A tale of three PKCs: epsilon emerges as a driver of pre-neoplastic phenotypes.
Cell Cycle. 2011 Feb 1;10(3):379. Epub 2011 Feb 1. No abstract available.
Comstock CE, Augello MA, Schiewer MJ, Karch J, Burd CJ, Ertel A, Knudsen ES, Jessen WJ,
Aronow BJ, Knudsen KE. Cyclin D1 is a selective modifier of androgen-dependent signaling and
androgen receptor function. J Biol Chem. 2011 Mar 11;286(10):8117-27. Epub 2011 Jan 5.
Jensen RB, Brokner C, Knudsen KE, Tauson AH. A comparative study of the apparent total tract
digestibility of carbohydrates in Icelandic and Danish warmblood horses fed two different
haylages and a concentrate consisting of sugar beet pulp and black oats. Arch Anim Nutr. 2010
Oct;64(5):343-56.
Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock
CE, Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE. The retinoblastoma tumor
suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest.
2010 Dec 1;120(12):4478-92. doi: 10.1172/JCI44239. Epub 2010 Nov 22.
Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES. RB-pathway disruption in
breast cancer: differential association with disease subtypes, disease-specific prognosis and
therapeutic response. Cell Cycle. 2010 Oct 15;9(20):4153-63. Epub 2010 Oct 27.
Nilsson AC, Östman EM, Knudsen KE, Holst JJ, Björck IM. A cereal-based evening meal rich in
indigestible carbohydrates increases plasma butyrate the next morning. J Nutr. 2010
Nov;140(11):1932-6. Epub 2010 Sep 1.
INVITED SEMINARS:
2009
Mount Sinai School of Medicine, Oncological Sciences
2009
University of Toledo, Biochemistry and Oncological Sciences
2009
Mayo Clinic College of Medicine, Urology, Biochemistry and Molecular Biology
2009
University of Maryland, Pathology
2009
University of Delaware, Cancer Center
59
2009
University of Kansas Medical Center, Cancer Center
INVITED PRESENTATIONS:
2009
Endocrine Society Meeting (to accept the Richard E. Weitzman Award)
2009
Gordon Conference, Hormone Action
2009
Society for Basic Urologic Research
2010
Keystone Nuclear Receptor Symposium (*speaker and co-organizer)
TEACHING:
2009 Lead Instructor, Genetics Program Journal Club/Data Analyses Course
(200802.GE.720.01)
COMMITTEES:
2007-present
2007-present
2007-present
2008-present
Member, Kimmel Cancer Center
Member, EMHAC Program
Director, Greater Philadelphia Prostate Cancer Working Group
Member, Genetics PhD Program Graduate Committee
Editorial Activities:
2006-present Editorial Board, Molecular Cancer Therapeutics
2007-present Associate Editor, Endocrine Related Cancer
2007-present Senior Editor, Cancer Research
2008-present Editorial Board, The Prostate
2008-present Editorial Board, American Journal of Pathology
Memberships and Positions in Professional and Academic Societies:
National Societies
American Association for Cancer Research (Active Member 2000-present)
Endocrine Society (Active Member, 2004-present)
Society for Basic Urologic Research (Active Member, 2005-present)
National Scientific Committees:
NIH Cancer & Molecular Pathobiology study section, (Ad hoc 2004-05; Member 2006-present)
AACR Annual Meeting Committee, Exhibits (Member, 2009-present)
Scientific Advisory Board, Delaware INBRE program
International Scientific Committees
Australian Prostate Cancer Research Centre, University of Adelaide (2008-present)
Jamaican Disaspora Committee on Cancer Prevention (2008-present)
60
Hilary Koprowski, M.D.
Professor
1. Description of Research
Production of safe, effective and inexpensive vaccines preferably for needlefree
routes of immunization
2.
d.
e.
f.
g.
h.
3.
Current Research Projects
a. Microbicides For Prevention of HIV Infection
b. Needle-Free Vaccine Against Cervical Cancer
c. Antibodies for the Treatment of Cancer and Development of
Cancer Vaccine
Needle-Free Smallpox Vaccine
Poliomyelitis Vaccine – New Generation
Improved DPT Vaccine
Commercial Fish Vaccine
Multiple Sclerosis
Grant Support
U.S. Department of Agriculture
$97,561
Development of Chimeric Plant Viruses to Express Full Length Therapeutic Proteins in Plants. Main goal:
To develop and test new strategies and plant expression systems for the production of vaccines and
other biomedical products for the prevention and treatment of animal diseases.
Commonwealth of Pennsylvania
$500,000
Department OF Health
Production of Plant-based Vaccines and other Biomedical Against AIDS and Other Diseases. Main goal:
Production of human and animal vaccines and other biopharmaceuticals in plants.
PENDING:
Title: Tobacco Biomass for Biofuel Production, Both Ethanol and Biodiesel
Agency: Department of Environmental Production, Commonwealth of Pennsylvania
Principal Investigator: Hilary Koprowski
Main goal: To develop a technological basis for the subsequent production of ethanol and diesel biofuels
using green tobacco biomass.
4.
Future Plans
We will perfect a vaccine against uterine cancer through plant biotechnology using vaginal
suppositories. Complete the development of poliomyelitis vaccine based on immunization
of the world population with plant-derived virus-like particles instead of living virus. Improvement in
the extraction procedure of fuel oil from biomass for commercial use.
5.
Committees
Committee on Committees
61
6.
Publications
(July 1, 2009 to June 30, 2010)
Andrianov, Vyacheslav, Nikolai Borysyuk, Natalia Progrebnyak, Anita Brinker,
Joseph Dixon, Sergei Spitsin, John Flynn, Paulina Matyszczuk, Karolina Andryszak,
Marilyn Laurelli, Maxim Golovkin and Hilary Koprowski. 2009. Tobacco as a production
platform for biofuel: overexpression of Arabidopsis DGAT and LEC2 genes increases accumulation and
shifts the composition of lipids in green biomass. Plant Biotechnology
Journal 8: 1-11.
7.
Book Chapters and Reviews
8.
Presentations
9/28/09
Lecture by Dr. Koprowski in Atlanta, GA at the Centers for Disease Control
(CDC) World Rabies Day. Title: “Rabies.”
10/19/09:
Lecture by Dr. Koprowski in Quebec City, Canada at the “Rabies in the Americas
Meeting.” Title: “Experience with Rabies over the Past 60 Years.”
9.
Editorial Positions
i. Springer Verlag’s “Current Topics in Microbiology & Immunology”
ii. “DNA and Cell Biology”
10.
Memberships
American Academy of Arts and Sciences
National Academy of Sciences
Foreign Member, Yugoslav Academy of Arts and Sciences
Foreign Member, Polish Academy of Sciences
Foreign Member, Russian Academy of Medical Sciences
Fellow, The Polish Institute of Arts and Sciences of America, Inc.
Foreign Member, Finnish Society of Sciences and Letters, Section of Biosciences
Fellow, Royal Society of Medicine, London England
College of Physicians of Philadelphia
New York Academy of Medicine
New York Academy of Sciences (President 1959)
American Association for the Advancement of Sciences
American Association for Cancer Research
American Association of Anatomists
American Federation for Medical Research
American Medical Association
American Society for Cell Biology
American Society for Microbiology
American Society for Neurochemistry
American Society for Virology
62
Lucia R. Languino
Professor
1.
Description of Research
Dr. Languino investigates the role of cell adhesion receptors in phenotypic
changes of prostate cancer cells. A strong research focus is being devoted to
the study of the cross-talk between cell adhesion molecules, extracellular
matrix proteins and growth factor receptors in vitro and in vivo systems and
how this cross-talk affects intracellular signal transduction, cell survival, cell
migration and cell division. Dr. Languino's research interests also focus on
the cellular and molecular characterization of the metastatic process of
prostate cancer with particular emphasis on the signals directing distant
localization of prostate cancer cells.
2. Grant Support
R01CA89720 (Languino)
$261,630
03/01/2001 – 04/30/2015
Integrin Signaling Pathways In Prostate Cancer
R01CA109874 (Languino)
$260,730
Beta1 Integrins And Igf-L Receptor In Prostate Cancer
09/01/2004 - 02/29/2016
P01CA140043 (Languino)
$213,470
Integrin Regulation Of Prostate Cancer Progression
07/01/2011 – 06/30/2012
3. Publications (2010-2011)
Sayeed A, Alam N, Trerotola M, Languino LR. Insulin-like growth factor 1 stimulation of androgen
receptor activity requires β(1A) integrins. J Cell Physiol. 2011 Apr 4. doi: 10.1002/jcp.22784.
[Epub ahead of print]
Kang BH, Tavecchio M, Goel HL, Hsieh CC, Garlick DS, Raskett CM, Lian JB, Stein GS, Languino LR,
Altieri DC. Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic
prostate cancer growth in a genetic mouse model of disease. Br J Cancer. 2011 Feb
15;104(4):629-34. Epub 2011 Feb 1.
Kang BH, Siegelin MD, Plescia J, Raskett CM, Garlick DS, Dohi T, Lian JB, Stein GS, Languino LR,
Altieri DC. Preclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors,
gamitrinibs, in advanced prostate cancer. Clin Cancer Res. 2010 Oct 1;16(19):4779-88. Epub
2010 Sep 28.
Lee WH, Hung MC, Iczkowski KA, Languino LR, Dubinett SM, Wang D. Editorial Board 2010
American Journal of Translational Research (ISSN 1943-8141): www.ajtr.org Publisher: e-Century
Publishing Corporation (www.e-Century.org). Am J Transl Res. 2010 Jul 30;2(4):458-62.
Goel HL, Underwood JM, Nickerson JA, Hsieh CC, Languino LR. Beta1 integrins mediate cell
proliferation in three-dimensional cultures by regulating expression of the sonic hedgehog
effector protein, GLI1. J Cell Physiol. 2010 Jul;224(1):210-7.
63
Zhiping Li
Assistant Professor
1.
Description of Research
Cyclin D1 is best known as the regulatory subunit of a dimeric holoenzyme
including the cell cycle-dependent kinase CDK4, which phosphorylates and
inactivates the retinoblastoma protein Rb to promote progression through
the G1-S phase of the cell cycle. In addition to regulating the cell cycle,
cyclin D1 regulates angiogenesis, lipogenesis, and mitochondrial function.
Overexpression of the cyclin D1 has been reported in a variety of human
cancers including breast, colon, prostate, and hematopoietic malignancies. In invasive breast cancers,
cyclin D1 is overexpressed in up to 50% of cases. The cyclin D1 gene consists of 5 distinct exons. Human
cyclin D1 is expressed as two isoforms derived by alternate RNA splicing. The canonical isoform is
termed as cyclin D1a. The alternatively spliced isoform is termed as cyclin D1b, which differ for the
inclusion of intron 4 in the D1b mRNA. In cells, cyclin D1b has an increased transforming capacity.
Cellular migration is essential for developmental morphogenesis, tissue repair, and tumor metastasis.
My previous studies in Dr. Richard G. Pestell’s lab reveal that cyclin D1 acts to promote cellular
migration by inhibiting Rho/ROCK signaling and expression of thrombospondin-1 (TSP-1), an
extracellular matrix protein that regulates cell migration in many settings including cancer (Molecular
and Cellular Biology. 2006; 26(11): 4240-56). It has been shown that p27KIP1 has a pro-migratory function
through inhibiting RhoA activity. My previous study also indicates that cyclin D1 promotes cellular
migration via up-regulating p27KIP1 abundance and physical interaction with p27KIP1 (Cancer Research.
2006; 66(20): 9986-94). Alternate cyclin D1 mRNA splicing modulates p27KIP1 binding and cell migration
(Journal of Biological Chemistry 2008; 283(11): 7007-15).
2. Current Research Projects
Currently I am studying the role of cyclin D1 in DNA damage response and its implication in
colon cancer adjuvant chemotherapy.
3. Future Plans
(1). The Role of Cyclin D1 in Breast Cancer Angiogenesis
(2). The Role of Cyclin D1 in DNA Damage Response
4. Publications (2009-)
Velasco-Velázquez MA, Li Z, Casimiro M, Loro E, Homsi N, Pestell RG. Examining the role of cyclin D1 in
breast cancer. Future Oncol. 2011 Jun;7(6):753-65.
Meng H, Tian L, Zhou J, Li Z, Jiao X, Li WW, Plomann M, Xu Z, Lisanti MP, Wang C, Pestell RG. PACSIN 2
represses cellular migration through direct association with cyclin D1 but not its alternate splice form
cyclin D1b. Cell Cycle. 2011 Jan 1;10(1):73-81. Epub 2011 Jan 1.
Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG.
Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer Res. 2010
Nov 1;70(21):8802-11. Epub 2010 Oct 12.
5. Teaching
I technically help junior faculty, postdoctoral fellows or students in their experiments.
64
Jack W. London, Ph.D.
Research Professor
1.
Description of Research
Biomedical informatics, with emphasis on clinical research and pathology
informatics.
2.
Current Research Projects
Development of a research data warehouse which combines phenotype and “omic” data. Study of the
work flow architecture of the cancer clinical trial development and conduct. Extension of tools for
biospecimen data management and sharing.
3.
Grant Support
NCI caBIG® funding (3 contracts).
Delaware Health Science Alliance (DHSA) funding for research data warehouse development.
4.
Future Plans
Expand pilot research data warehouse to a federated network of research resources for DVICTS.
5.
Committees
TJU Information Technology Security Committee
TJU Technical Architecture Directions Group
University I.T. Council
6.
Publications (most recent)
London J.W., Smalley K.S., Conner K., and Smith J.B. The Automation of Clinical Trial Serious Adverse
Event Reporting Workflow. Clinical Trials 6:446-454. (2009).
7.
Memberships
American Medical Informatics Association
Association for Computing Machinery
65
Amy K. McClendon, Ph.D.
Research Instructor
1.
Publications
McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ,
Witkiewicz A, Addya S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES. RB and
p53 Cooperate to Prevent Liver Tumorigenesis in Response to Tissue Damage.
Gastroenterology. 2011 Jun 24. [Epub ahead of print]
Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast
cancer: key mechanisms of response and failure. Oncogene. 2010 Jul 15;29(28):4018-32. Epub 2010 May
17.
66
Steven B. McMahon Ph.D.
Associate Professor of Cancer Biology
1.
Description of Research
Function of the MYC oncogene. Genetic alterations targeting the myc
oncogene are the most common transforming events in human cancer.
These alterations cause overexpression of the transcription factor MYC. A
thorough understanding of the MYC transcription network is critical to
progress against cancer. Despite intensive study, the essential genes lying
downstream of MYC remain poorly understood. Of the 629 reported MYC
target genes, only 6 have documented roles in MYC-mediated
transformation. An expression-profiling screen that utilized a discrete
mutant of MYC was used to selectively identify those targets relevant to transformation. This screen
identified 40 novel MYC targets and studies have begun to validate their importance in MYC-driven
tumorigenesis. For example, shRNA-mediated depletion of the novel target MTA1 blocks the increased
invasiveness of tumor cells caused by MYC. MTA1 reportedly controls the epithelial-to-mesenchymal
transition; however its link to MYC was previously unknown. Additional targets from the screen (BAG-1,
POLRMT and CD30), were characterized at the molecular level and are now being characterized to
determine the biological function they contribute during MYC-mediated transformation. The aim of this
study is to understand the biological roles played by MTA1, BAG-1, POLRMT and CD30 in MYC-driven
tumors. Together, these studies are likely to identify new cellular functions for MYC, including
regulating invasiveness, blocking the anti-tumor immune response and inhibiting the apoptotic stimuli
generally associated with oncogene overexpression. Using well-defined systems in which human cells
can be transformed by the MYC oncoprotein in vitro, each of the targets identified will be dissected in
order to understand the precise advantage they provide to MYC-driven tumor cells.
Post-translational regulation of the p53 tumor suppressor. The p53 tumor suppressor pathway is
inactivated in most forms of human cancer. In normal cells, p53 is maintained at low levels by
ubiquitylation and subsequent proteosome-mediated degradation. In addition to ubiquitylation, p53 is
regulated by other forms of post-translational modification, including phosphorylation, acetylation and
methylation. These modifications regulate a variety of p53 functions, including protein half-life, DNA
binding capacity and cofactor interaction. The elimination of p53 function is critical during human
carcinogenesis because the normal role of p53 is to induce either cell cycle arrest or apoptosis when a
cell sustains genetic damage. As the central regulator of apoptotic cell death, the p53 pathway is of
critical importance for chemotherapeutic strategies that induce genotoxic damage. Understanding the
key events in the p53/apoptosis pathway is therefore of broad clinical significance.
We recently demonstrated that p53 is acetylated at a unique site, K120, within the DNA binding
domain, by the MYST family acetyltransferases hMOF and TIP60. Acetylation at K120 occurs rapidly
after DNA damage and several lines of evidence confirm that it is an essential event during p53dependent apoptosis. We have further shown that the acetyl-K120 form of p53 is enriched at proapoptotic target genes, but not cell cycle arrest targets like p21. In addition, mutation of the acetylation
site to arginine (K120R) inhibits apoptosis, without blocking cell cycle arrest. Our evidence also suggests
that the acetyl-K120 form of p53 has functions outside the nucleus, perhaps via the regulation of BCL2
family interactions at the mitochondrial outer membrane. Remarkably, the inactivation of p53 by K120R
mutation has been reported in a small number of human tumors, and both the enzymes that catalyze
K120 acetylation (i.e. hMOF and TIP60) are lost in human tumors as well. These observations suggest
that the activation of the K120-acetylation pathway may be an important tumor suppressor mechanism.
67
Our current model suggests that MYST family proteins acetylate p53 at K120 after DNA damage. This
acetylation somehow enhances the ability of p53 to selectively activate the transcription of apoptotic
target genes. Simultaneously, acetylation of K120 provides p53 with increased apoptotic function at the
mitochondria. Thus, our data suggest that K120 acetylation coordinates the nuclear and mitochondrial
arms of the p53/apoptosis pathway. Three questions are being pursues. First, we will define the events
that regulate K120 acetylation in response to DNA damage. Second, we will define the molecular
requirement for the acetylation of K120 during the transcription of pro-apoptotic targets of p53. Finally,
we will determine what essential function is played by K120 acetylation in the non-transcriptional
function of p53 at the mitochondria.
Regulation of chromatin and transcription by the ubiquitin hydrolase encoded by the cancer stem
cell marker USP22. The rapid increase in transcription that cells undergo in response to extracellular
signals requires that sequence-specific activators dynamically overcome repressive chromatin structures
at their targets. This is often accomplished by the recruitment of enzymatic complexes that modify or
displace local nucleosomes. In yeast and humans, the SAGA complex is among the most thoroughly
studied of these transcriptional co-activators. Previously described activities of SAGA include histone
acetylation and TBP/TATA stabilization. Recently, studies, first in yeast and then humans, identified a
ubiquitin hydrolase module that targets ubiquitylated H2B in yeast and both H2A and H2B in humans.
Our studies of the human enzyme, termed USP22, also demonstrated that it is required for appropriate
progression through the G1 phase of the cell cycle. Concurrently, USP22 was shown to be a member of
an 11 gene “polycomb signature” whose expression could accurately predict human cancers with the
cancer stem cell-like properties of rapid relapse, resistance to therapy and increased metastatic
potential. Polycomb proteins comprise transcription co-repressor complexes, which function in part via
the ubiquitylation of H2A at K119. Also in the “cancer stem cell signature” is the polycomb protein
RING1b, which is the E3 ligase responsible for ubiquitylation of H2A by Polycomb Complex 1. A second
link to polycomb came from studies of the drosophila ortholog of USP22 that revealed a role for this
protein in blocking heterochromatin formation/position-effect-variegation, a well-established
polycomb-mediated effect.
Among the issues that remain poorly understood regarding USP22 are; why is de-ubiquitylation of
H2A-K119 and/or H2B-K120 required for activator-driven transcription? are histones the relevant
substrates that explain the role of USP22 in transcription and cell cycle progression? what is the
functional interplay between USP22 and polycomb proteins during tumorigenesis and stem cell selfrenewal? and what cell cycle event requires USP22 in order for proper G1 progression? Four projects
are proposed to broaden our understanding of USP22 function. These include: (1) What specific defect
explains the block to activator-driven transcription in USP22 depleted cells? (2) What are the direct
genomic and proteomic targets/substrates of USP22? (3) Why does USP22 depletion lead to G1 cell
cycle arrest? and (4) What is the relationship between USP22 and polycomb proteins in normal and
cancer stem cells? Given the genetic and biochemical links between USP22 and polycomb, it seems
likely that a thorough understanding of USP22 function will provide significant insight into basic
mechanisms of transcriptional regulation and the emerging area of cancer stem cell biology.
2. Current Research Projects
Defining the role of MYC in the metabolic reprogramming that accompanies malignant transformation.
Defining survival signals that protect tumors cells from MYC-mediated apoptosis.
Understanding the link between DNA damage signals and activation of the p53 tumor suppressor
protein.
Characterization of enzymes that regulate epigenetic programs in normal and cancer stem cells.
3. Grant Support
68
NIH/NCI R01 CA 90465 (Dr. S. McMahon)
05/01/02-04/30/13
Role of Acetyltransferases in Transformation by c-MYC
NIH/NCI R21 CA152786 (Dr. S. McMahon)
07/01/10-06/30/12
Function of a novel, sirtuin-regulated acetylation site on p53.
NIH/NCI R01 CA 098172 (Dr. S. McMahon)
07/01/03-06/30/09 (comp. renewal pending)
Role of TRRAP in the p53-Medicated Transcription of mdm2 competitive renewal submitted 11/09
Research Support (Dr. S. McMahon)
2009-present (unrestricted)
CellCentric Ltd., Chesterford Research Park, Cambridge, UK
4. Future Plans
Establish Programmatic Research Projects in the following areas:
a.) Molecular Determinants of Breast Cancer Stem Cell Function
b.) Dissection of Survival Pathways in Human Cancer
c.) DNA Damage and p53 Signaling in Prostate and Breast Cancer
5. Committees
NIH Grant Review Panel, Cancer Genetics, 2010 (ad hoc)
National Cancer Institute of Canada Review Panel
AIRC - Italian Association for Cancer Research Grant Review Panel
NIH Challenge Grant (RC1) Review Panel ZRG1 GGG-F (58)
NIH/NIEHS Outstanding New Environmental Scientist Grant Review Panel, 2010 (ad hoc)
Finland Academy Research Council for Health Grant Review Panel
NJ Commission on Cancer Research Grant Review Panel
AACR Journals - Emerging Technologies Task Force
External Examiner-Watson School of Biological Sciences, Cold Spring Harbor Laboratories
TJU-Cancer Biology Dept. Committee for Faculty Recruitment (Chair)
TJU-Kimmel Cancer Center Committee for Cancer Center Membership (Co-Chair)
Admissions Committee - Graduate Program in Cell and Developmental Biology
Organizing Committee - 15th International p53 Conference
6. Publications
Charvet C, Wissler M, Brauns-Schubert P, Wang SJ, Tang Y, Sigloch FC, Mellert H, Brandenburg
M, Lindner SE, Breit B, Green DR, McMahon SB, Borner C, Gu W, Maurer U. Phosphorylation of
Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53. Mol Cell. 2011 Jun
10;42(5):584-96.
Sussman RT, Zhang XY, McMahon SB. Enzymatic assays for assessing histone deubiquitylation
activity. Methods. 2011 Jul;54(3):339-47. Epub 2011 Apr 12.
Heinzmann S, McMahon SB. New molecules for the treatment of pain. Curr Opin Support Palliat
Care. 2011 Jun;5(2):111-5. Review.
D'Mello R, Marchand F, Pezet S, McMahon SB, Dickenson AH. Perturbing PSD-95 Interactions
With NR2B-subtype Receptors Attenuates Spinal Nociceptive Plasticity and Neuropathic Pain.
Mol Ther. 2011 Mar 22. [Epub ahead of print]
69
Carter LM, McMahon SB, Bradbury EJ. Delayed treatment with chondroitinase ABC reverses
chronic atrophy of rubrospinal neurons following spinal cord injury. Exp Neurol. 2011
Mar;228(1):149-56. Epub 2011 Jan 6.
Mellert HS, Stanek TJ, Sykes SM, Rauscher FJ 3rd, Schultz DC, McMahon SB. Deacetylation of the
DNA-binding domain regulates p53-mediated apoptosis. J Biol Chem. 2011 Feb 11;286(6):426470. Epub 2010 Dec 9.
La Rocca G, Shi B, Audia A, Ferrari-Amorotti G, Mellert HS, Calabretta B, McMahon SB, SeppLorenzino L, Baserga R. Regulation of microRNA-145 by growth arrest and differentiation. Exp
Cell Res. 2011 Feb 15;317(4):488-95. Epub 2010 Nov 25.
Aggarwal P, Vaites LP, Kim JK, Mellert H, Gurung B, Nakagawa H, Herlyn M, Hua X, Rustgi AK,
McMahon SB, Diehl JA. Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers
neoplastic growth via activation of the PRMT5 methyltransferase. Cancer Cell. 2010 Oct
19;18(4):329-40.
Kaan TK, Yip PK, Patel S, Davies M, Marchand F, Cockayne DA, Nunn PA, Dickenson AH, Ford AP,
Zhong Y, Malcangio M, McMahon SB. Systemic blockade of P2X3 and P2X2/3 receptors
attenuates bone cancer pain behaviour in rats. Brain. 2010 Sep;133(9):2549-64.
Bishop T, Marchand F, Young AR, Lewin GR, McMahon SB. Ultraviolet-B-induced mechanical
hyperalgesia: A role for peripheral sensitization. Pain. 2010 Jul;150(1):141-52. Epub 2010 May
15.
7. Editorial Positions
Associate Editor: American Journal of Pathology (2009-present)
Editorial Board Member: Journal of Biological Chemistry (2010-present)
8. Teaching
Course Co-Director - Genetics 720/730:Advanced Topics in Genetics
Lecturer - Genetics 636:Regulation of Cell Cycle and Apoptosis
Lecturer - Genetics 652:Molecular Basis of Cancer
Lecturer - Biochemistry 612:Advanced Topics in Protein Function
9. Memberships
American Association for Cancer Research
American Association for the Advancement of Science
American Society for Microbiology
American Society for Biochemistry and Molecular Biology
70
2009-present
2007-present
2007-present
2010-present
Maria T. Nevalainen, M.D., Ph.D.
Associate Professor
1.
Description of Research
Dr. Nevalainen's research program focuses on Stat transcription factors
in castration-resistant growth and metastatic dissemination of prostate
cancer.
2.
Current Research Projects
a) The molecular mechanisms underlying synergy between Stat5 and
androgen receptor in prostate cancer.
b) Chemical modifications of the small-molecule pharmacological Stat5a/b inhibitor.
c) Small-molecule Jak2 inhibitor AZD1480 in prostate cancer therapy in laboratory models of prostate
cancer.
d) Stat5 as a modifier of prostate cancer cell sensitivity to radiation therapy.
e) Stat5 in metastatic behavior of prostate cancer cells in vitro and in vivo metastases models.
f) Somatic changes of Stat5 genes during prostate cancer progression: Stat5a/b as an oncogene.
g) Stat5a/b in promotion of prostate cancer cell growth during hypoxia.
3.
Grant Support
Ongoing Support:
Principal Investigator: Sponsored Research Contract; “Therapeutic Targeting of Stat5 and Stat3 in
Human Prostate Cancer by AZD1480; Astra Zeneca.
Co-Principal Investigator: American Cancer Society Institutional Research Grant (IRG-114958), Thomas
Jefferson University; Kimmel Cancer Center; (PI: Richard Pestell).
Principal Investigator: Idea Development Award; “Interaction of Transcription Factor Stat5 with
Androgen Receptor in Growth Promotion of Prostate Cancer”, Department of Defense Prostate Cancer
Research Program.
Principal Investigator: RO1-Grant (RCA11358A); “Stat5 in Progression of Prostate Cancer”, NCI, TCB
Study Section.
Completed Support:
Principal Investigator: Idea Development Award; “Stat3 in Metastatic Progression of Prostate Cancer”,
Department of Defense Prostate Cancer Research Program.
Principal Investigator: New Investigator Award; “Stat5 a Therapeutic Target Protein for Prostate Cancer”,
Department of Defense Prostate Cancer Research Program.
Principal Investigator, Research Scholar Grant; “Androgen-Independent Growth Signaling Pathways in
Prostate Cancer”, American Cancer Society.
71
Collaborator, NIH U54 CA100970-01, PI; Leena Hilakivi-Clarke.
Principal Investigator, Investigator Initiated Grant; “Lipid Modulation of Jak2-Stat5 Signal Transduction
Pathway in Prostate Cancer”, American Institute for Cancer Research.
Principal Investigator: Lombardi Comprehensive Cancer Center Developmental Funds,
“Jak2 - Stat5 Signaling in Prostate Cancer”.
Principal Investigator: Research Award for Prostate Cancer Research; “Stat5 as a Critical Survival Factor
in Prostate Cancer”, American Cancer Society, IRG 97-152-11.
4.
Future Plans
a) University City Science Center “QED” funding
b) RO1 “Stat5 in progression of prostate cancer” – competitive renewal.
c) RC4 NCI, NIH: Development of small-molecule Stat5a/b inhibitors for prostate cancer therapy – new
grant.
d) RO1 “Stat5 in prostate cancer metastases – NCI, new grant.
5.
Committees
2007 – Present Member, Executive Committee of Kimmel Cancer Center
2006 – Present Member, Committee on Research.
2009 – Present Member of the Research Advisory Committee, Thomas Jefferson University
2009 – Present Member of the Dean’s Faculty Forward Task Force, Thomas Jefferson University
2007 – Present Oversight Committee for Small Molecular Screening Resource (Kimmel Cancer
Center)
2008 – Present Professorial Faculty Advisory Committee (Thomas Jefferson University)
2007 – Present Kimmel Cancer Center Training Committee (Chair)
2008 – Present Member of the PhD-Thesis Committee of Xiang Wang (PI: Linda Siracusa, PhD)
2009 – Present Member of the PhD- Thesis Committee of Supriya Shah (PI: Karen Knudsen, PhD)
2009 – Present Member of the PhD- Thesis Committee of Ankur Sharma (PI: Karen Knudsen, PhD)
6.
Publications
Sato T, Neilson LM, Peck AR, Liu C, Tran TH, Witkiewicz A, Hyslop T, Nevalainen MT, Sauter G, Rui
H. Signal transducer and activator of transcription-3 and breast cancer prognosis. Am J Cancer
Res. 2011;1(3):347-355.
Koptyra M, Gupta S, Talati P, Nevalainen MT. Signal transducer and activator of transcription
5a/b: Biomarker and therapeutic target in prostate and breast cancer. Int J Biochem Cell Biol.
2011 Oct;43(10):1417-21. Epub 2011 Jun 17.
Peck AR, Witkiewicz AK, Liu C, Stringer GA, Klimowicz AC, Pequignot E, Freydin B, Tran TH, Yang N,
Rosenberg AL, Hooke JA, Kovatich AJ, Nevalainen MT, Shriver CD, Hyslop T, Sauter G, Rimm DL,
Magliocco AM, Rui H. Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer
predicts poor clinical outcome and increased risk of antiestrogen therapy failure. J Clin Oncol.
2011 Jun 20;29(18):2448-58. Epub 2011 May 16.
Liao Z, Nevalainen MT. Targeting transcription factor Stat5a/b as a therapeutic strategy for
prostate cancer. Am J Transl Res. 2011 Feb;3(2):133-8. Epub 2010 Nov 21.
Dagvadorj A, Tan SH, Liao Z, Xie J, Nurmi M, Alanen K, Rui H, Mirtti T, Nevalainen MT. N-terminal
truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate
cancer cells. Int J Biochem Cell Biol. 2010 Dec;42(12):2037-46. Epub 2010 Sep 18.
72
7.
Presentations
“Stat5 Signaling Pathway in Prostate Cancer Progression and as a Therapeutic Target for Advanced
Prostate Cancer”. 19th Meeting of European Association of Urological Research (ESUR), October 7-9,
2010.
“Curing Prostate Cancer: A Task for a Woman”. Thomas Jefferson University: “A Celebration of
Jefferson Women” March 16, 2010.
“Stat5 in Progression of Prostate Cancer and as a Target Protein for Therapy Development”. Columbia
University, NewYork, NY. (October 30, 2009)
“Stat5 in Prostate Cancer Progression: Prospects for Pharmacological Targeting”. KCC Joint Faculty
Seminar Series, Thomas Jefferson University. (October 26, 2009)
“Transcription Factor Stat5a/b as a Therapeutic Target Protein for Prostate Cancer”. Department of
Cancer Biology, University of Massachusetts Medical School, Worcester, MA October 14, 2009
“Autocrine Prl-Jak2-Stat5 Pathway Promotes Growth and Progression of Prostate Cancer”. Gordon
Conference; Hormone Action in Development and Cancer. Plymouth, NH (July 26-31, 2009)
"Transcription Factor Stat5a/b as a Therapeutic Target Protein for Prostate Cancer.” AstraZeneca,
Waltham, MA (April 2-3, 2009)
“Transcription Factor Stat5 as a Therapeutic Target Protein for Prostate Cancer.” 5th Annual National
Symposium on Prostate Cancer, Clark-Atlanta University, Atlanta, GA (March 15-17, 2009)
8.
Editorial Positions
2010 – Present, Research and Reports in Biology, Member of the Honorary Editorial Board.
2010 – Present, International Journal of Clinical and Experimental Pathology, Member of the Senior
Editorial Board.
2009 – Present, International Journal of Biochemistry and Cell Biology, Senior Editor.
2008 – Present, American Journal of Pathology, Member of the Editorial Board.
9.
Memberships
American Association for Cancer Research: 1999 –
International Cytokine Society: 1999 –
Endocrine Society: 1999 –
American Association for the Advancement of Science: 1994 –
73
Marzena J. Pedrini, Ph.D.
Research Instructor
1. Description of Research
The focus of my work is to understand the differences in the mechanisms
responsible for peroxynitrite-dependent opening of the blood-brain barrier
(BBB) during a Central Nervous System (CNS) immune/inflammatory
response.
The BBB is a specialization of the vasculature which is less permeable than
the vasculature of the periphery. Alteration in BBB integrity is seen in
various noninflammatory neurological diseases, such as certain types of brain cancer, and in association
with the invasion of circulating immune/inflammatory cells into the CNS, as is the case for multiple
sclerosis. Although enhanced BBB permeability is central to the development of a pathological CNS
inflammatory response, changes in BBB permeability can also occur without clinical signs during a
protective CNS immune response. Using CNS trauma, the clearance of an attenuated neurotrophic virus,
and experimental allergic encephalomyelitis an animal correlate of multiple sclerosis (MS) as models, we
are investigating the immune mechanisms that modulate BBB function. We have shown that urate, a
peroxynitrite-dependent radical scavenger, can prevent BBB permeability and cell invasion into the CNS.
Currently we are concentrating on the mechanisms through which peroxynitrite-dependent radicals i)
alter BBB integrity and ii) promote cell invasion through the brain parenchyma.
2. Current Research Projects
1. Characterization of the processes involved in delivering rabies virus specific immune effectors
across the blood-brain barrier, an element of the response known to be deficient in animals
infected with lethal rabies virus strains.
3. Grant Support
1. NIH 1 U01 AI083046-01, Principal Investigator, D.C. Hooper, Ph.D.
4. Future Plans
The objective of the research program is to develop strategies to deliver therapeutic cells and factors
into brain tissue in response to infection and cancer and to control this in autoimmune/non-specific
conditions. Plans include obtaining independent funding for work related to MS and participate in the
development of brain tumor models in the lab.
74
Richard G. Pestell, MB, BS, MD, PhD, FACP, FRACP
Chair, Department of Cancer Biology
1.
Description of Research: Molecular mechanisms and gene therapy of
breast and prostate cancer.
Our research activities focus on understanding the mechanisms governing
cell-cycle regulated gene transcription and the role of these proteins in
tumorigenesis and differentiation. The cyclin D1 gene encodes a regulatory
subunit of a holoenzyme that phosphorylates and inactivates the tumor
suppressor protein pRB (retinoblastoma protein) resulting in release of the
pRB binding proteins and transcription factors, E2Fs. Several cyclin dependent kinase inhibitors (CDKI),
p16/p19 block this activity of cyclin D1. Cyclin D1 plays a critical role in tumorigenesis and
differentiation.
Because the abundance of the cyclin D1 gene is rate-limiting in progression through the cell-cycle in cells
that contain the pRB protein, we have delineated the molecular mechanisms regulating the cyclin D1
gene. We demonstrated that cyclin D1 kinase (CDK) activity and cyclin D1 promoter activity is induced by
o-ncogenes (p21ras, Rac, dbl, v-src, Neu-also known as ErbB-2), growth factors and G-protein coupled
receptors. The transcription factors (E2Fs,JUN/Fos, CREB, ATF2/ETS), coactivators (p300/CBP,Brg/Brm1)
and scaffolding proteins (JIP1, caveolins) coordinate this induction.
Using retroviral and lentiviral expression systems we are examining the requirement for specific cyclins
and CKI for induction and progression of breast and prostate tumors induced by o-ncogenes. These
systems are used to examine treatment synergy with conventional therapies.
We have developed tissue-specific inducible transgenic expression systems and are using this transgenic
approach to examine the role of cyclin D1, the CDKI in breast and prostate cancer.
Using knockout mice we are examining the role of CDKI in breast cancer induced by specific o-ncogenes
and synergy with conventional therapies.
2. Grant Support
P30 CA 056036-09 (Pestell)
NIH
$2,897,417
Translational Research in Cancer
Cancer Center Support Grant
06/22/95-05/31/13
$3,116,058/yr
3 calendar
(Total $15,580,290)
R01 CA 075503-13 (Pestell)
NIH
$247,624
Initiation and Maintenance in Mammary Tumorigenesis
06/05/98-07/31/12
$382,579/yr
0.6 calendar
(Total $1,913,927)
R01 CA 070896-14 (Pestell)
NIH
$192,695
Regulation of Cyclin D1 Expression
09/18/06-07/31/11
$307,598/yr
0.6 calendar
(Total $1,537,990)
75
R01 CA 120876-01A (Lisanti)
NIH
$190,615
CAV-1 Epithelial-Stromal Interactions and Breast Cancer
Role: Co-Investigator (50% Pestell, 50% Lisanti)
08/03/07-07/31/12
$294,500/yr
1.2 calendar
(Total $1,472,500)
R01 CA 086072-09 (Pestell)
NIH
$250,000
Androgen Receptor Function in Prostate Cancer
04/01/00-03/31/14
$386,250 /yr
1.2 calendar
(Total $1,931,250)
R01 CA 132115-02 (Pestell)
07/01/09-06/30/11
NIH
$207,500/yr
DACH1/Eya Cell-fate Determination Factor and Mammary Tumorigenesis
1.2 calendar
(Total $830,000)
R01 CA 137494-01A2 (Knudsen, E)
NIH
Impact of Cyclin D1 Isoforms in Breast Cancer
08/01/10-01/31/15
-0- calendar
(Total $160,294)
P30 CA 056036-10S1 (Pestell)
NIH
Translational Research in Cancer
Cancer Center Support Grant
06/22/95-05/31/13
$63,390/yr
-0- calendar
(Total $63,390)
P30 CA 056036-10S2 (Pestell)
NIH
Translational Research in Cancer
Cancer Center Support Grant
06/22/95-05/31/13
$98,650/yr
-0- calendar
(Total $98,650)
P30 CA 056036-10S3 (Pestell)
NIH
Translational Research in Cancer
Cancer Center Support Grant
09/01/09-08/31/10
$154,500/yr
-0- calendar
(Total $154,500)
P30 CA 056036-10S4 (Pestell)
NIH
Translational Research in Cancer
Cancer Center Support Grant
09/01/09-08/31/10
$50,002/yr
-0- calendar
(Total $50,002)
P30 CA 056036-10S5 (Pestell)
NIH
Translational Research in Cancer
Cancer Center Support Grant
09/01/09-08/31/10
$956,943/yr
-0- calendar
(Total $956,943)
R01CA137494-01 (E. Knudsen, Pestell)
NIH
Impact of Cyclin D1 Isoforms in Breast Cancer
12/01/08-11/30/13
$386,250/year
-0- calendar
(Total $1,931,250)
76
(Pestell)
07/01/06-06/30/11
Falk Trust
$500,000
$500,000/yr
The Role of MicroRNA Gene Expression in Human Breast Cancer
-0- calendar
(Total $2,500,000)
080-03800-F8 1101 (Pestell Lab)
01/01/08-12/31/10
Margaret Q. Landenberger Research Foundation
$150,000
$150,000/yr
DACH-Six-Eya Pathway in Breast Cancer Proliferation and Metastasis
(Pestell)
01/01/08-12/31/10
-0- calendar
(Total $450,000)
IRG-08-060-02 (Pestell)
American Cancer Society
Institutional Research Grant
(Total $210,000)
01/01/08-12/31/11
$210,000/yr
$210,000
N/A
SAP#4100034615 (Pestell)
07/26/07-12/31/10
N/A
Commonwealth of PA/Dept. of Health $740,000
$740,000
(Total $740,000)
Identification of a new class of genes that contributes to the development of breast cancer
SAP#4100047652 (Pestell)
01/01/09- 12/31/12
N/A
Commonwealth of PA/Dept. of Health $500,000
$427,800
(Total $427,800)
Identification of a new class of genes that contributes to the development of breast cancer
SAP#4100050910 (Pestell)
Commonwealth of PA/Dept. of Health $500,000
Genetic Targets of Breast Tumors Initiating Cells
01/01/10- 12/31/13
$553,261
N/A
(Total $553,261)
6. Publications July 2010 to June 2011
1.
Martinez-Outschoorn, U., Balliet, R., Rivadeneira, D., Chiavarina, B., Pavlides, S., Wang, C.,
Whitaker-Menezes, D., Daumer, K., Lin, Z., Witkiewicz, A., Flomenberg, N., Howell, A., Pestell, R.,
Knudsen, E., Sotgia, F., Lisanti M.P. Oxidative stress in cancer fibroblasts drives tumor-stroma coevolution: A new paradigm for understanding tumor metabolism, the field effect and genomic
instability in cancer cells. Cell Cycle. 2010 Aug 15;9(16):3256-76. Epub 2010 Aug 28.
2.
Pavlides, S., Tsirigos, A., Migneco, G., Whitaker-Menezes, D., Chiavarina, B., Flomenberg, N.,
Frank, P.G., Casimiro, M.C., Wang, C., Pestell R.G., Martinez-Outschoorn, U.E., Howell, A., Sotgia,
F., Lisanti M.P. The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone
production in fueling tumor cell metabolism. Cell Cycle. 2010 September 1;9(17). [Epub ahead of
print].
3.
Bonuccelli, G., Tsirigos, A., Whitaker-Menezes, D., Pavlides, S., Pestell, R.G., Chiavarina, B.,
Frank, P.G., Flomenberg, N., Howell, A., Martinez-Outschoorn, U.E., Sotgia, F., Lisanti, M.P.
Ketones and lactate “fuel” tumor growth and metastasis: Evidence that epithelial cancer cells use
oxidative mitochondrial metabolism. Cell Cycle. 2010 Sep;9(17):3506-14. Epub 2010 Sep 21.
4.
Martinez-Outschoorn U.E., Casey, T., Lin, Z., Whitaker-Menezes, D., Chiavarina, B., Zhou, J.,
Wang, C., Pavlides, S., Martinez-Cantarin, M.P., Capozza, F., Witkiewicz, A.K., Flomenberg, N.,
Howell, A., Pestell, R.G., Caro, J., Lisanti, M.P., Sotgia, F. Autophagy in cancer associated
fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the
tumor stromal microenvironment. Cell Cycle. 2010 Sep;9(17):3515-33. Epub 2010 Sep 9.
77
5.
Chiavarina, B., Whitaker-Menezes , D., Migneco, G., Martinez-Outschoorn, U.E., Pavlides, S.,
Howell, A., Tanowitz, H.B., Casimiro, M.C., Wang, C., Pestell, R.G., Grieshaber, P., Caro, J.,
Sotgia, F., Lisanti, M.P. HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts,
and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific
oncogenesis. Cell Cycle. 2010 Sep;9(17):3534-51. Epub 2010 Sep 4.
6.
Baur J.A., Chen D., Chini E.N., Chua K., Cohen H.Y., de Cabo R., Deng C., Dimmeler S., Gius D.,
Guarente L.P., Helfand S.L., Imai S., Itoh H., Kadowaki T., Koya D., Leeuwenburgh C., McBurney
M., Nabeshima Y., Neri C., Oberdoerffer P., Pestell R.G., Rogina B., Sadoshima J., Sartorelli V.,
Serrano M., Sinclair D.A., Steegborn C., Tatar M., Tissenbaum H.A., Tong Q., Tsubota K., Vaquero
A., Verdin E. Dietary restriction: Standing up for sirtuins. Science. 2010 Aug 27;329(5995):1012-3;
author reply 1013-4.
7.
Liu, M., Sakamaki, T., Casimiro, M., Willmarth, N., Quong, A., Ju, X., Ojeifo, J., Jiao, X., Yeow, WS., Wang, C., Katiyar, S., Shirley, L., Albanese, C., Joyce, D., Pestell, R.G. The canonical NF-κB
pathway governs mammary tumorigenesis in transgenic mice via tumor stem cell expansion.
Cancer Res. 2010 Dec 15;70(24):10464-10473.
8.
Li, Z., Jiao, X., Wang, C., Shirley, L.A., Elsaleh, H., Dahl, O., Wang, M., Soutoglou, E., Knudsen,
E.S., Pestell, R.G. Alternative Cyclin D1 Splice Forms Differentially Regulate the DNA Damage
Response. Cancer Res. 2010 Nov 1;70(21):8802-11. Epub 2010 Oct 12.
9.
Gaughan, L., Stockley, J., Wang, N., McCracken, S.R.C., Treumann, A., Armstrong, K., Watt, K.,
McEwan, I.J., Wang, C., Pestell, R.G., Robson, C.N. Regulation of the androgen receptor by SET9mediated methylation. Nucleic Acids Res. Epub 2010 Oct 19.
10.
Katiyar, S., Casimiro, M., Dettin, L., Ju, X., Wagner, E.W., Tanaka, H., and Pestell, R.G. C-jun
inhibits mammary apoptosis in vivo. Mol Biol Cell. 2010 Dec;21(23):4264-74. Epub 2010 Oct 6.
11.
Trimmer, C., Whitaker-Menezes, D., Bonuccelli, G., Milliman, J.N., Daumer, K.M., Aplin, A.E.,
Pestell, R.G., Sotgia, F., Lisanti, M.P., Capozza, F. CAV1 Inhibits Metastatic Potential in
Melanomas through Suppression of the Integrin/Src/FAK Signaling Pathway. Cancer Res. 2010
Oct 1;70(19):7489-99. Epub 2010 Aug 13.
12.
Wu, K., Jiao, X., Li, Z., Katiyar, S., Casimiro, M.C., Yang, W., Zhang, Q., Willmarth, N.E., Chepelev,
I., Crosariol, M., Wei, Z., Li, A., Zhao, K., Pestell, R.G. The Cell-Fate Determination Factor
Dachshund Reprograms Breast Cancer Stem Cell Function. J Biol Chem. 2010 Oct 11. [Epub
ahead of print].
13.
Zhou, J., Wang, C., Zhang, W., Popov, V.M., Wang, M., Pattabiraman, N., Sune, C., Pestell, R.G.
Transcription elongation regulator 1 is a co-integrator of the cell fate determination factor
Dachshund homolog 1. J Biol Chem. 2010 Dec 17;285(51):40342-50. Epub 2010 Oct 18.
14.
Gaughan, L., Stockley, J., Wang, N., McCracken, S.R., Treumann, A., Armstrong, K., Shaheen, F.,
Watt, K., McEwan, I.J., Wang, C., Pestell, R.G., Robson, C.N.
Regulation of the androgen
receptor by SET9-mediated methylation. Nucleic Acids Res. Epub 2010 Oct 19.
15.
Marampon, F., Gravina, G.L., Di Rocco, A., Bonfili, P., Di Staso, M., Fardella, C., Polidoro, L.,
Ciccarelli, C., Festuccia, C., Popov, V.M., Pestell, R.G., Tombolini, V., Zani, B.M. MEKs/ERKs
inhibitor U0126 increases the radiosensitivity of rhabdomyosarcoma cells in vitro and in vivo by
down regulating growth and DNA repair signals. Mol Cancer Ther. 2011 Jan;10(1):159-68.
16.
Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Trimmer
C, Tsirigos A, Migneco G, Witkiewicz AK, Balliet R, Mercier I, Wang C, Flomenberg N, Howell A,
Lin Z, Caro J, Pestell RG, Sotgia F, Lisanti MP. The autophagic tumor stroma model of cancer or
"battery-operated tumor growth": A simple solution to the autophagy paradox. Cell Cycle. 2010
Nov;9(21):4297-306. Epub 2010 Nov 30.
17.
Gravina, G.L., Festuccia, C., Marampon, F., Popov, V.M., Pestell, R.G., Zani, B.M., Tombolini, V.
Biological rationale for the use of DNA methyltransferase inhibitors as new strategy for modulation
of tumor response to chemotherapy and radiation. Mol Cancer. 2010 Nov 25;9(1):305. [Epub
ahead of print]
78
18.
Meng, H., Tian, L., Zhou, J., Li, Z., Jiao, X., Li, W. W., Plomann, M., Xu, Z., Wang, C., and Pestell,
R.G. PACSIN 2 Represses Cellular Migration through Direct Association with Cyclin D1 but not its
Alternate Splice Form Cyclin D1b. Cell Cycle. 2011 Jan 1;10(1):73-81. Epub 2011 Jan 1.
19.
Powell, M.J., Casimiro, M.C., Cordon-Cardo, C., He, X., Yeow, W.S., Wang, C., McCue, P.,
McBurney, M.W., Pestell, R.G. Disruption of a Sirt1 Dependent Autophagy Checkpoint in the
Prostate Results in Prostatic Intraepithelial Neoplasia Lesion Formation. Cancer Res. 2011 Feb
1;71(3):964-75. Epub 2010 Dec 28.
20.
Wang, C., Tian, L., Popov, V. M., Pestell, R.G. Acetylation and Nuclear Receptor Action. J
Steroid Biochem Mol Biol. 2011 Feb;123(3-5):91-100. Epub 2010 Dec 15.
21.
Trimmer C., Sotgia F., Whitaker-Menezes D., Balliet R., Eaton G., Martinez-Outschoorn U.E.,
Pavlides S., Howell A., Iozzo R.V., Pestell R.G., Scherer P.E., Capozza F., Lisanti M.P. Caveolin1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal
microenvironment: A new genetically tractable model for human cancer associated fibroblasts.
Cancer Biol Ther. 2011 Feb 15;11(4). [Epub ahead of print]
22.
Bonuccelli G, Whitaker-Menezes D, Castello-Cros R, Pavlides S, Pestell RG, Fatatis A, Witkiewicz
AK, Heiden MG, Migneco G, Chiavarina B, Frank PG, Capozza F, Flomenberg N, MartinezOutschoorn UE, Sotgia F, Lisanti MP. The reverse Warburg Effect: Glycolysis inhibitors prevent
the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts. Cell Cycle.
2010 Dec 14;9(10):1960-71. Epub 2010 May 15.
23.
Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, Lisanti MP.
Stromal-Epithelial Metabolic Coupling in Cancer: Integrating Autophagy and Metabolism in the
Tumor Microenvironment. Int J Biochem Cell Biol. 2011 Feb 4. [Epub ahead of print]
24.
Janowski E, Jiao X, Katiyar S, Lisanti MP, Liu M, Pestell RG, Morad M. C-jun is required for TGF2
β-Mediated Cellular Migration via nuclear CA + Signaling. Int J Biochem Cell Biol. 2011 Mar 22.
[Epub ahead of print]
25.
Li SC, Acevedo J, Schwartz PH, Wang L, Jiang H, Luo J, Pestell RG, Loudon WG, Chang AC.
Mechanisms for Progenitor Cell-mediated Repair for Ischemic Heart Injury. Curr Stem Cell Res
Ther. 2011 Apr 5. [Epub ahead of print]
26.
Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N,
Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP. Ketones and lactate increase cancer
cell "stemness," driving recurrence, metastasis, and poor clinical outcome in breast cancer:
Achieving personalized medicine via Metabolo-Genomics. Cell Cycle. 2011 Apr 15;10(8). [Epub
ahead of print]
27.
Velasco-Velázquez MA, Popov VM, Lisanti MP, Pestell RG. The Role of Breast Cancer Stem
Cells in Metastasis and Therapeutic Implications. Am J Pathol. 2011 May. Review.
28.
Velasco-Velázquez MA, Li Z, Casimiro MC, Loro E, Homsi N, Pestell RG. Examining the role of
cyclin D1 in breast cancer. Future Oncol. 2011 Jun.
29.
Martinez-Outschoorn UE, Whitaker-Menezes D, Lin Z, Flomenberg N, Howell A, Pestell RG,
Lisanti MP, Sotgia F. Cytokine production and inflammation drive autophagy in the tumor
microenvironment: Role of stromal caveolin-1 as a key regulator. Cell Cycle. 2011 Jun 1;10(11).
[Epub ahead of print].
30.
Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK,
Birbe RC, Howell A, Pavlides S, Gandara R, Pestell RG, Sotgia F, Philp NJ, Lisanti MP. Evidence
for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in
cancer-associated fibroblasts. Cell Cycle. 2011 Jun 1;10(11). [Epub ahead of print].
31.
DeAngelis T, Wu K, Pestell RG, Baserga R. The type 1 insulin-like growth factor receptor and
resistance to DACH1. Cell Cycle. 2011 Jun 15;10(12). Report. [Epub ahead of print].
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32.
Castello-Cros R, Bonnuccelli G, Molchansky A, Capozza F, Witkiewicz AK, Birbe RC, Howell A,
Pestell RG, Whitaker-Menezes D, Sotgia F, Lisanti MP. Matrix remodeling stimulates stromal
autophagy, “fueling” cancer cell mitochondrial metabolism and metastasis. Cell Cycle. 2011 Jun
15;10(12). [Epub ahead of print].
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Michael Prosniak, Ph.D.
Research Instructor
1.
Description of Research
The goal of my project is to better understand the mechanisms of
immunosuppression in malignant gliomas – the most common primary central
nervous system neoplasms. I examined the hypothesis that malignant cells
attract monocytes from the circulation into the tumor bed and promote a
subset to differentiate into M2 anti-inflammatory macrophages. To test this
hypothesis I analyzed the expression of tumor-specific and immune cell molecular markers in tissue
specimens from patients with low and high-grade malignant gliomas. Different methods, including
quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR), immunohistochemical and
FACS analysis were utilized. The results obtained suggest that M2-macrophages may have an important
contribution to immunosuppression observed in patients with high-grade gliomas.
2.
Current Research Projects
PI: D. Andrews
Co-investigators: Dr. D.C. Hooper, Dr. L. Harshyne, Dr. P. Flomenberg
Private grant: Paparone Foundation
Period: 2002 through 2010 years
Purpose: Establishment of prospective archival database including microarray analyses for patients with
malignant primary brain tumors.
Amount: $50 000 per year per lab
3.
Future Plans
I will continue to study the molecular mechanisms of immunosuppression and try to determine the
origin of subsets of cells produced anti-inflammatory and immunosuppressive cytokine IL-10.
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Andrew A. Quong
Associate Professor
Current Academic Appointment
Cancer Biology
Secondary Appointment
Otolaryngology
Description of Research
My laboratory is focused in two areas. In the first, we are interested in the role of kinases in migration
and invasion and in particular their role in breast cancer metastasis. In the second, we are interested in
developing new assays for the early diagnosis, measurement of response to therapy and stratification of
patients to therapy. In both of these areas we use mass spectrometry and high-pressure liquid
chromatography to identify changes in protein levels. In addition, we are developing new
computational techniques to analyze these large datasets that will provide new insight into the
mechanisms of the changes in the observed cellular phenotype.
Current Research Projects
Systems Approach to Predicting Response to Combination Therapy
Breast Cancer Metastasis: The Role of Cyclin D1
Diagnostic and Prognostic Tests for Breast Cancer
Estrogen Receptor, BRCA1 and Tamoxifen Response
Proteomics of Papillary Thyroid Cancer
Grant Support
Pa Department of Health, Breast Cancer Research Foundation, NCI
Publications
Liu, M., Sakamaki, T., Casimiro, M., Willmarth, N., Quong, A., Ju, X., Ojeifo, J., Jiao, X., Yeow,
W-S., Wang, C., Katiyar, S., Shirley, L., Albanese, C., Joyce, D., Pestell, R.G. The canonical NFκB pathway governs mammary tumorigenesis in transgenic mice via tumor stem cell expansion.
Cancer Res. 2010 Dec 15;70(24):10464-10473.
Teaching
Proteomics
Committees
Jefferson Medical College Committee on Research
Memberships
AACR, ASBMB, ASMS
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Hallgeir Rui, M.D., Ph.D.
Professor
1. Description of Research
Dr. Rui has made a series of contributions to increased
understanding of the molecular mechanisms of signal transduction
by receptors for prolactin and related cytokines and hormones. Dr.
Rui was the first to isolate a prolactin receptor-associated tyrosine
kinase, and to identify this molecule as Janus kinase-2. Dr. Rui’s
laboratory has maintained a focus on prolactin receptor function
with a primary goal of understanding the role of downstream JakStat pathways and their aberrations in breast cancer. Progress
includes recognition of the prolactin-induced Jak2-Stat5 pathway as a pro-differentiation pathway in
human breast cancer, which during progression of human breast cancer is aberrantly regulated.
Activation of Stat5 is a highly favorable prognostic marker in node-negative breast cancer and an
invasion-suppressive role of Stat5 in human breast cancer may explain the mechanism of the favorable
prognosis associated with active Stat5 in early stage breast cancer. Efforts to study the gene targets of
Stat5a and Stat5b are ongoing. Dr. Rui and his team have also invented and applied a new technology to
generate high density tissue arrays for high-through-put in situ biomarker studies. This technology is
being combined with in situ quantitative immunoprofiling of tumors. Dr. Rui is the PI of a $6.7 million, 5
year Promise Grant from Komen for the Cure to classify breast cancer tumors based on expression of
druggable target proteins for improved personalized cancer care. Dr. Rui is also supported by NCI to
explore the utility of hormonally humanized mice engineered by the laboratory for improved drug
response testing of human breast cancer in vivo.
2. Current Research Projects
“Therapy-relevant Stratification of Breast Cancer Patients: Integrating Pathology and
Biomarker Analyses” (PI: Rui, H.)
The Aims of this project are 1) to use quantitative immunohistochemistry to map expression levels of a
panel of 250 therapy-relevant markers across 5,000 clinical breast cancer specimens, and 2) carry out a
biomarker-driven phase I/II clinical trial of the combined growth factor inhibitor and anti-angiogenic
agent, motesanib.
“Experimental Modeling of Human Breast Cancer in Mice” (PI: Rui, H.)
The goal of this project is to explore the utility of human prolactin expressing mice as a recipient for
human breast cancer xenotransplants. Specific Aims: 1) Determine the effect of physiological levels of
circulating human prolactin on growth and biology of established metastasis-derived human breast
cancer lines in vivo; 2) Determine the role of human PRL and the stability of PRL receptors in modulating
the sensitivity of human breast cancer cells to anti-cancer drugs; 3) Establish new transplantable human
breast cancer models and evaluate hPRL mice as recipients for primary breast cancer directly from
patients.
“Stat5 as a gatekeeper in human breast cancer metastasis” (PI: Rui, H.)
The goal of this project is to use in vitro and in vivo approaches to experimentally test the hypothesis
that Stat5 acts as a suppressor of metastatic escape of tumor cells from primary breast cancer. The
studies do not aim to determine the causes of loss of active Stat5 in breast cancer. The studies maintain
a strict focus on Jak2-Stat5 and do not do not investigate the role of other signaling pathways in breast
cancer. Specific Aims: 1) Determine the correlation between Stat5 activation in clinical breast cancer and
outcome, 2) Investigate whether Stat5 activation has invasive suppressive effects in breast cancer, 3)
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use Jak2 mammary cells and to determine whether Jak2 affects invasion and metastasis of breast cancer
in vivo.
“Regulation of CXCR4 Signaling” (PI: Benovic, J.)
The goal of this project is to investigate the role of CXCR4 signaling in breast cancer growth and
progression involving tumor array analyses of clinical specimens. The Aim related to Dr. Rui is to study
these molecules in clinical breast cancer specimens, to determine whether CXCR4 signaling is correlated
with increased tumor invasion and higher grade.
“CAV-1, Stat5a Signaling and Estrogen-Dependent Breast Cancer” (PI: Lisanti, M.)
The Aim related to Dr. Rui’s effort is whether to investigate in clinical specimens whether mutation/loss
of Cav-1 is associated with increased activation of Stat5 and ER expression.
“CAV-1, A Novel Mammary Gland Tumor Suppressor Gene” (PI: Sotgia, F.)
The goal of this proposal is to investigate the role of Caveolin-1 as a regulator of Jak2-Stat5 signaling and
tumorigenesis in mammary gland cancer. The Aim related to Dr. Rui’s involvement is to determine
levels of Cav-1 and other markers of invasive phenotype in clinical human breast cancer.
3. Grant Support
Susan G. Komen for the Cure Promise Award $6,700,000 ($ 1,300,000/yr)
01/08/10 - 01/07/15
Therapy-relevant Stratification of Breast Cancer Patients: Integrating Pathology and Biomarker Analyses
PI – Rui. 12% effort.
NIH R01 CA118740
$1,000,000 ($200,000/yr)
04/01/08 - 03/31/13
Experimental Modeling of Human Breast Cancer in Mice. PI – Rui. 20% effort.
Susan G. Komen Foundation Award KG070129 $180,000 ($ 60,000/yr) 07/01/08 - 06/30/11
Humanized Mouse Model for Analysis of Human Breast Cancer Xenotransplants PI- Rui.
PA Breast Cancer Coalition Award #08-2008-02
$ 50,000
07/01/09-06/30/10
Control of Stat5 activity in breast cancer. PI- Rui.
One year bridge funding for project reviewed favorably by NCI.
NIH 5 R01 129626-03 $ 250,000
07/01/07-06/30/12
Regulation of CXCR4 Signaling PI - Benovic, J., Co-Investigator 5% effort.
NIH 5 R01 CA098779 $ 250,000
07/01/07-06/30/12
CAV-1, Stat5a Signaling, and Estrogen-Dependent Breast Cancer
PI - Lisanti, M., Co-Investigator. 5% effort.
American Cancer Society RSG-08-081-01-MGO $ 200, 000
01/01/08-12/31/11
CAV-1, A Novel Mammary Gland Tumor Suppressor Gene
PI – Sotgia, F. Co investigator at
5% effort.
4. Future Plans
Future plans center on building on established collaborations with surgeons, medical oncologists,
pathologists, biostatisticians, and bioinformaticists to accelerate the translational aspects of the
laboratory’s research. 1) Therapy-relevant profiling of protein networks in breast cancer and other
cancers; 2) strengthened focus on bioinformatics and biomedical informatics to cope with complex
biological and clinical datasets; and 3) facilitate new biomarker-guided clinical trials at KCC that will
involve rational recruitment of patients who are likely responders to new targeted therapies.
5. Committees
TJU/KCC Committees
Kimmel Cancer Center Executive Committee, Member
Leader, Kimmel Cancer Center Endocrine Mechanisms and Hormone Action Program
MD/PhD Graduate Program oversight committee, member
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Cell Biology and Development Graduate Program, member
Cell Biology and Development Graduate Program oversight committee, member
Faculty Search Committee, Department of Cancer Biology, member
Faculty Search Committee, Cancer Prevention, Control and Population Science, member
Department Review, University Review Committee for Department of Microbiology and Immunology
6. Publications
Sato T, Neilson LM, Peck AR, Liu C, Tran TH, Witkiewicz A, Hyslop T, Nevalainen MT, Sauter G,
Rui H. Signal transducer and activator of transcription-3 and breast cancer prognosis. Am J
Cancer Res. 2011;1(3):347-355.
Huangfu WC, Qian J, Liu C, Liu J, Lokshin AE, Baker DP, Rui H, Fuchs SY. Inflammatory signaling
compromises cell responses to interferon alpha.
Oncogene. 2011 Jun 13. doi:
10.1038/onc.2011.221. [Epub ahead of print]
HuangFu WC, Qian J, Liu C, Rui H, Fuchs SY. Melanoma cell-secreted soluble factor that
stimulates ubiquitination and degradation of the interferon alpha receptor and attenuates its
signaling. Pigment Cell Melanoma Res. 2010 Dec;23(6):838-40.
Peck AR, Witkiewicz AK, Liu C, Stringer GA, Klimowicz AC, Pequignot E, Freydin B, Tran TH, Yang
N, Rosenberg AL, Hooke JA, Kovatich AJ, Nevalainen MT, Shriver CD, Hyslop T, Sauter G, Rimm
DL, Magliocco AM, Rui H. Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast
cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure. J Clin
Oncol. 2011 Jun 20;29(18):2448-58. Epub 2011 May 16.
Li D, Zhao Y, Liu C, Chen X, Qi Y, Jiang Y, Zou C, Zhang X, Liu S, Wang X, Zhao D, Sun Q, Zeng Z,
Dress A, Lin MC, Kung HF, Rui H, Liu LZ, Mao F, Jiang BH, Lai L. Analysis of MiR-195 and MiR-497
expression, regulation and role in breast cancer. Clin Cancer Res. 2011 Apr 1;17(7):1722-30.
Epub 2011 Feb 24.
Michal AM, Peck AR, Tran TH, Liu C, Rimm DL, Rui H, Benovic JL. Differential expression of
arrestins is a predictor of breast cancer progression and survival. Breast Cancer Res Treat. 2011
Feb 12. [Epub ahead of print]
Lee KI, Rui H, Pastor RW, Im W. Brownian dynamics simulations of ion transport through the
VDAC. Biophys J. 2011 Feb 2;100(3):611-9.
Rui H, Lee KI, Pastor RW, Im W. Molecular dynamics studies of ion permeation in VDAC. Biophys
J. 2011 Feb 2;100(3):602-10.
Arendt LM, Rugowski DE, Grafwallner-Huseth TA, Garcia-Barchino MJ, Rui H, Schuler LA.
Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer.
Breast Cancer Res. 2011 Jan 28;13(1):R11. [Epub ahead of print]
Cao X, Wang Q, Liu Q, Rui H, Liu H, Zhang Y. Identification of a luxO-regulated extracellular
protein Pep and its roles in motility in Vibrio alginolyticus. Microb Pathog. 2011 Feb;50(2):12331. Epub 2010 Dec 15.
Behling KC, Tang A, Freydin B, Chervoneva I, Kadakia S, Schwartz GF, Rui H, Witkiewicz AK.
Increased SIAH expression predicts ductal carcinoma in situ (DCIS) progression to invasive
carcinoma. Breast Cancer Res Treat. 2011 Oct;129(3):717-24. Epub 2010 Nov 19.
Varghese B, Swaminathan G, Plotnikov A, Tzimas C, Yang N, Rui H, Fuchs SY. Prolactin inhibits
activity of pyruvate kinase M2 to stimulate cell proliferation. Mol Endocrinol. 2010
Dec;24(12):2356-65. Epub 2010 Oct 20.
Johnson KJ, Peck AR, Liu C, Tran TH, Utama FE, Sjolund AB, Schaber JD, Witkiewicz AK, Rui H.
PTP1B suppresses prolactin activation of Stat5 in breast cancer cells. Am J Pathol. 2010
Dec;177(6):2971-83. Epub 2010 Oct 15.
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Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES. RB-pathway disruption in
breast cancer: differential association with disease subtypes, disease-specific prognosis and
therapeutic response. Cell Cycle. 2010 Oct 15;9(20):4153-63. Epub 2010 Oct 27.
Jo S, Rui H, Lim JB, Klauda JB, Im W. Cholesterol flip-flop: insights from free energy simulation
studies. J Phys Chem B. 2010 Oct 28;114(42):13342-8.
Dagvadorj A, Tan SH, Liao Z, Xie J, Nurmi M, Alanen K, Rui H, Mirtti T, Nevalainen MT. Nterminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in
prostate cancer cells. Int J Biochem Cell Biol. 2010 Dec;42(12):2037-46. Epub 2010 Sep 18.
Richards NG, Rittenhouse DW, Freydin B, Cozzitorto JA, Grenda D, Rui H, Gonye G, Kennedy EP,
Yeo CJ, Brody JR, Witkiewicz AK. HuR status is a powerful marker for prognosis and response to
gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients. Ann
Surg. 2010 Sep;252(3):499-505; discussion 505-6.
Rui H, Im W. Protegrin-1 orientation and physicochemical properties in membrane bilayers
studied by potential of mean force calculations. J Comput Chem. 2010 Dec;31(16):2859-67.
Witkiewicz AK, Freydin B, Chervoneva I, Potoczek M, Rizzo W, Rui H, Brody JR, Schwartz GF,
Lisanti MP. Stromal CD10 and SPARC expression in ductal carcinoma in situ (DCIS) patients
predicts disease recurrence. Cancer Biol Ther. 2010 Aug;10(4):391-6. Epub 2010 Aug 21.
Jepkorir G, Rodríguez JC, Rui H, Im W, Lovell S, Battaile KP, Alontaga AY, Yukl ET, Moënne-Loccoz
P, Rivera M. Structural, NMR spectroscopic, and computational investigation of hemin loading in
the hemophore HasAp from Pseudomonas aeruginosa.
J Am Chem Soc. 2010 Jul
21;132(28):9857-72.
Rui H, Cao S, Shang H, Jin P, Wang K, Zheng Y. Effects of heat treatment on internal browning
and membrane fatty acid in loquat fruit in response to chilling stress. J Sci Food Agric. 2010
Jul;90(9):1557-61.
7. Editorial Positions
Associate Editor - American Journal of Pathology
Chair or Member, thesis committee for the following students:
Member of thesis committee for Rachael Dippold, TJU. Mentor Jan Hoek.
Member of thesis committee for Stephanos Pavlides, TJU. Mentor Michael Lisanti
Member of Thesis committee for Daniele Christiano, TJU. Mentor Michael Lisanti.
Member of Thesis committee for Dayana Rivadnera, TJU. Mentor Erik Knudsen.
Chair of Thesis committee for Casey Trimmer, TJU. Mentor Michael Lisanti.
Member of PhD thesis committee for Jeffrey Schmidt, University of Nebraska Medical Center,
Mentor: Kay-Uwe Wagner.
Member of Thesis committee for Jeff Dean, TJU. Mentor Erik Knudsen.
Lecturing:
“Jak2 Mutations in Hematopoietic Malignancies” GE652 Molecular Basis of Cancer (2h).
“Jak-Stat signaling in Cancer.” CB611 Advanced topics in Cell Biology (4h).
8. Memberships
Endocrine Society
American Association for Cancer Research
American Association for the Advancement of Science
Fulbright Alumni Association
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87
Federica Sotgia, PhD
Assistant Professor
1.
Description of Research
Recently, we proposed a new model for understanding the Warburg
effect in tumor metabolism. Our hypothesis is that epithelial cancer
cells induce the Warburg effect (aerobic glycolysis) in neighboring
stromal fibroblasts. These cancer-associated fibroblasts, then undergo
myo-fibroblastic differentiation, and secrete lactate and pyruvate
(energy metabolites resulting from aerobic glycolysis). Epithelial
cancer cells could then take up these energy-rich metabolites and use
them in the mitochondrial TCA cycle, thereby promoting efficient energy production (ATP
generation via oxidative phosphorylation), resulting in a higher proliferative capacity. In this
alternative model of tumorigenesis, the epithelial cancer cells instruct the normal stroma to
transform into a wound-healing stroma, providing the necessary energy-rich microenvironment for facilitating tumor growth and angiogenesis. In essence, the fibroblastic tumor
stroma would directly feed the epithelial cancer cells, in a type of host-parasite relationship.
We have termed this new idea the "Reverse Warburg Effect." In this scenario, the epithelial
tumor cells "corrupt" the normal stroma, turning it into a factory for the production of energyrich metabolites. This alternative model is still consistent with Warburg's original observation
that tumors show a metabolic shift towards aerobic glycolysis. In support of this idea, unbiased
proteomic analysis and transcriptional profiling of a new model of cancer-associated fibroblasts
(caveolin-1 (Cav-1) deficient stromal cells), shows the upregulation of both (1) myo-fibroblast
markers and (2) glycolytic enzymes, under normoxic conditions. We validated the expression of
these proteins in the fibroblastic stroma of human breast cancer tissues that lack stromal Cav-1.
Importantly, a loss of stromal Cav-1 in human breast cancers is associated with tumor
recurrence, metastasis, and poor clinical outcome. Thus, an absence of stromal Cav-1 may be a
biomarker for the "Reverse Warburg Effect," explaining its powerful predictive value.
2. Current Research Projects
Previously, we proposed a new model for understanding the Warburg effect in tumorigenesis
and metastasis. In this model, the stromal fibroblasts would undergo aerobic glycolysis (a.k.a.,
the Warburg effect)--producing and secreting increased pyruvate/lactate that could then be
used by adjacent epithelial cancer cells as “fuel” for the mitochondrial TCA cycle, oxidative
phosphorylation, and ATP production. To test this model more directly, we used a matched set
of metabolically well-characterized immortalized fibroblasts that differ in a single gene. CL3
fibroblasts show a shift towards oxidative metabolism, and have an increased mitochondrial
mass. In contrast, CL4 fibroblasts show a shift towards aerobic glycolysis, and have a reduced
mitochondrial mass. We validated these differences in CL3 and CL4 fibroblasts by performing an
unbiased proteomics analysis, showing the functional upregulation of 4 glycolytic enzymes,
namely ENO1, ALDOA, LDHA, and TPI1, in CL4 fibroblasts. Many of the proteins that were
upregulated in CL4 fibroblasts, as seen by unbiased proteomics, were also transcriptionally
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upregulated in the stroma of human breast cancers, especially in the patients that were prone
to metastasis. Importantly, when CL4 fibroblasts were co-injected with human breast cancer
cells (MDA-MB-231) in a xenograft model, tumor growth was dramatically enhanced. CL4
fibroblasts induced a >4-fold increase in tumor mass, and a near 8-fold increase in tumor
volume, without any measurable increases in tumor angiogenesis. In parallel, CL3 and CL4
fibroblasts both failed to form tumors when they were injected alone, without epithelial cancer
cells. Mechanistically, under co-culture conditions, CL4 glycolytic fibroblasts increased
mitochondrial activity in adjacent breast cancer cells (relative to CL3 cells), consistent with the
“Reverse Warburg Effect”. Notably, Western blot analysis of CL4 fibroblasts revealed a
significant reduction in caveolin-1 (Cav-1) protein levels. In human breast cancer patients, a loss
of stromal Cav-1 is associated with an increased risk of early tumor recurrence, metastasis,
tamoxifen-resistance, and poor clinical outcome. Thus, loss of stromal Cav-1 may be an
effective marker for predicting the “Reverse Warburg Effect” in the stroma of human breast
cancer patients. As such, CL4 fibroblasts may be a new attractive model for mimicking the
“glycolytic phenotype” of cancer-associated fibroblasts.
3. Grant Support
Source:
American Cancer Society
RSG-MGO-114786/ RSG-08-081-01-MGO
Project Title:
CAV-1, A Novel Mammary Gland Tumor Suppressor Gene
Principal Investigator: Federica Sotgia, 50% effort
Dates of Project:
four years, 01/01/08-12/31/011
Total Direct Costs:
$800,000
Source:
Project Title:
Breast Cancer Alliance, Young Investigator Award
A Lactation-Based Approach for Breast Cancer Therapy and Prevention
Principal Investigator: Federica Sotgia
Dates of Project:
two years, 01/01/09-12/31/011
Total Direct Costs:
$125,000
4. Future Plans
Loss of stromal caveolin 1 (Cav-1) is a novel biomarker for cancer associated fibroblasts that
predicts poor clinical outcome in breast cancer and DCIS patients. We hypothesized that
epithelial cancer cells may have the ability to drive Cav-1 down-regulation in adjacent normal
fibroblasts, thereby promoting the cancer associated fibroblast phenotype. To test this
hypothesis directly, we are developing a novel co-culture model employing i) human breast
cancer cells (MCF7), and ii) immortalized fibroblasts (hTERT-BJ1), which are grown under
defined experimental conditions. Importantly, co-culture of immortalized human fibroblasts
with MCF7 breast cancer cells leads to Cav-1 down-regulation in fibroblasts. These results were
also validated using primary cultures of normal human mammary fibroblasts co-cultured with
MCF7 cells. In this system, we can show that Cav-1 down-regulation is mediated by lysosomal
degradation, as pre-treatment with lysosome-specific inhibitors rescues Cav-1 expression.
Functionally, fibroblasts co-cultured with MCF7 breast cancer cells acquire a cancer associated
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fibroblast phenotype, characterized by Cav-1 down-regulation, increased expression of
myofibroblast markers and extracellular matrix proteins, and constitutive activation of
TGF /Smad2 signaling. siRNA-mediated Cav-1 down-regulation mimics several key changes that
occur in co-cultured fibroblasts, clearly indicating that a loss of Cav-1 is a critical initiating
factor, driving stromal fibroblast activation during tumorigenesis. As such, this co-culture
system can now be used as an experimental model for generating “synthetic” cancer associated
fibroblasts (CAFs). More specifically, these “synthetic” CAFs could be used for drug screening to
identify novel therapeutics that selectively target the Cav-1-negative tumor micro-environment.
Our findings also suggest that chloroquine, or other lysosomal inhibitors, may be useful as anticancer agents, to therapeutically restore the expression of stromal Cav-1 in cancer associated
fibroblasts.
5. Committees
Co-Director, Translational Research Core Facility, Kimmel Cancer Center, Jefferson University
Member, Molecular Biology and Genetic Program, Kimmel Cancer Center, Jefferson University
6. Publications
Castello-Cros R, Bonnuccelli G, Molchansky A, Capozza F, Witkiewicz AK, Birbe RC, Howell A,
Pestell RG, Whitaker-Menezes D, Sotgia F, Lisanti MP. Matrix remodeling stimulates stromal
autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis. Cell Cycle. 2011 Jun
15;10(12):2021-34. Epub 2011 Jun 15.
Sotgia F, Martinez-Outschoorn UE, Lisanti MP. Mitochondrial oxidative stress drives tumor
progression and metastasis: should we use antioxidants as a key component of cancer treatment
and prevention? BMC Med. 2011 May 23;9:62.
Martinez-Outschoorn UE, Whitaker-Menezes D, Lin Z, Flomenberg N, Howell A, Pestell RG,
Lisanti MP, Sotgia F. Cytokine production and inflammation drive autophagy in the tumor
microenvironment: role of stromal caveolin-1 as a key regulator. Cell Cycle. 2011 Jun
1;10(11):1784-93. Epub 2011 Jun 1.
Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK,
Birbe RC, Howell A, Pavlides S, Gandara R, Pestell RG, Sotgia F, Philp NJ, Lisanti MP. Evidence for
a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in
cancer-associated fibroblasts. Cell Cycle. 2011 Jun 1;10(11):1772-83. Epub 2011 Jun 1.
Witkiewicz AK, Kline J, Queenan M, Brody JR, Tsirigos A, Bilal E, Pavlides S, Ertel A, Sotgia F,
Lisanti MP. Molecular profiling of a lethal tumor microenvironment, as defined by stromal
caveolin-1 status in breast cancers. Cell Cycle. 2011 Jun 1;10(11):1794-809. Epub 2011 Jun 1.
Martinez-Outschoorn UE, Pavlides S, Sotgia F, Lisanti MP. Mitochondrial biogenesis drives tumor
cell proliferation. Am J Pathol. 2011 May;178(5):1949-52. No abstract available.
Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N,
Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP. Ketones and lactate increase cancer cell
"stemness," driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving
personalized medicine via Metabolo-Genomics. Cell Cycle. 2011 Apr 15;10(8):1271-86.
Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N,
Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP. Ketones and lactate increase cancer cell
"stemness," driving recurrence, metastasis, and poor clinical outcome in breast cancer: Achieving
90
personalized medicine via Metabolo-Genomics. Cell Cycle. 2011 Apr 15;10(8). [Epub ahead of
print]
Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, Lisanti MP.
Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the
tumor microenvironment. Int J Biochem Cell Biol. 2011 Jul;43(7):1045-51. Epub 2011 Feb 15.
Llaverias G, Danilo C, Mercier I, Daumer K, Capozza F, Williams TM, Sotgia F, Lisanti MP, Frank
PG. Role of cholesterol in the development and progression of breast cancer. Am J Pathol. 2011
Jan;178(1):402-12. Epub 2010 Dec 23.
Trimmer C, Sotgia F, Whitaker-Menezes D, Balliet RM, Eaton G, Martinez-Outschoorn UE,
Pavlides S, Howell A, Iozzo RV, Pestell RG, Scherer PE, Capozza F, Lisanti MP. Caveolin-1 and
mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: a
new genetically tractable model for human cancer associated fibroblasts. Cancer Biol Ther. 2011
Feb 15;11(4):383-94. Epub 2011 Feb 15.
Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Casey T,
Tsirigos A, Migneco G, Witkiewicz A, Balliet R, Mercier I, Wang C, Flomenberg N, Howell A, Lin Z,
Caro J, Pestell RG, Sotgia F, Lisanti MP. The autophagic tumor stroma model of cancer or
"battery-operated tumor growth": A simple solution to the autophagy paradox. Cell Cycle. 2010
Nov 1;9(21):4297-306. Epub 2010 Nov 30. Review.
Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A,
Tanowitz HB, Casimiro MC, Wang C, Pestell RG, Grieshaber P, Caro J, Sotgia F, Lisanti MP. HIF1alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor
in breast cancer cells: Autophagy drives compartment-specific oncogenesis. Cell Cycle. 2010 Sep
1;9(17):3534-51. Epub 2010 Sep 4.
Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, Frank PG,
Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP. The
autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in
fueling tumor cell metabolism. Cell Cycle. 2010 Sep 1;9(17):3485-505.
Lisanti MP, Martinez-Outschoorn UE, Chiavarina B, Pavlides S, Whitaker-Menezes D, Tsirigos A,
Witkiewicz A, Lin Z, Balliet R, Howell A, Sotgia F. Understanding the "lethal" drivers of tumorstroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in
the tumor micro-environment. Cancer Biol Ther. 2010 Sep;10(6):537-42. Epub 2010 Sep 19.
Review.
Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C,
Pavlides S, Martinez-Cantarin MP, Capozza F, Witkiewicz AK, Flomenberg N, Howell A, Pestell
RG, Caro J, Lisanti MP, Sotgia F. Autophagy in cancer associated fibroblasts promotes tumor cell
survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal
microenvironment. Cell Cycle. 2010 Sep 1;9(17):3515-33. Epub 2010 Sep 9.
Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, Frank PG,
Flomenberg N, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Ketones and lactate
"fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative
mitochondrial metabolism. Cell Cycle. 2010 Sep 1;9(17):3506-14. Epub 2010 Sep 21.
Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C,
Whitaker-Menezes D, Daumer KM, Lin Z, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG,
Knudsen ES, Sotgia F, Lisanti MP. Oxidative stress in cancer associated fibroblasts drives tumorstroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and
genomic instability in cancer cells. Cell Cycle. 2010 Aug 15;9(16):3256-76. Epub 2010 Aug 28.
91
Trimmer C, Whitaker-Menezes D, Bonuccelli G, Milliman JN, Daumer KM, Aplin AE, Pestell RG,
Sotgia F, Lisanti MP, Capozza F. CAV1 inhibits metastatic potential in melanomas through
suppression of the integrin/Src/FAK signaling pathway. Cancer Res. 2010 Oct 1;70(19):7489-99.
Epub 2010 Aug 13.
Witkiewicz AK, Dasgupta A, Sammons S, Er O, Potoczek MB, Guiles F, Sotgia F, Brody JR, Mitchell
EP, Lisanti MP. Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple
negative and basal-like breast cancers. Cancer Biol Ther. 2010 Jul;10(2):135-43. Epub 2010 Jul 7.
7. Book Chapters and Reviews (from January 2009)
Witkiewicz AK, Casimiro MC, Dasgupta A, Mercier I, Wang C, Bonuccelli G, Jasmin JF, Frank PG, Pestell
RG, Kleer CG, Sotgia F, Lisanti MP. Towards a new "stromal-based" classification system for human
breast cancer prognosis and therapy. Cell Cycle. 2009 Jun 1;8(11):1654-8.
Gazzerro E, Sotgia F, Bruno C, Lisanti MP, Minetti C. Caveolinopathies: from the biology of caveolin-3 to
human diseases. Eur J Hum Genet. 2009 Dec;17(12):1692.
Bruno C, Sotgia F, Gazzerro E, Minetti C, Lisanti MP. Caveolinopathies. In: Pagon RA, Bird TC, Dolan CR,
Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993.2007 May 14.
8. Editorial Positions
Senior Assistant Editor, American Journal of Pathology
9. Teaching
Member, Jefferson College of Graduate Studies.
10. Memberships
Member, American Association for Cancer Reaserch
Member, American Association for Investigative Pathology
92
Fransiscus E. Utama
Research Instructor
1.
Description of Research
Primary research interest is in modeling human breast cancer in mice for
better predictors of drugs’ efficacy and safety. Also, discovering new
biomarkers to improve prediction of patients’ prognosis is being pursued.
2.
Current Research Projects
Generate primary human breast cancer cell lines for in vitro studies of breast cancer.
3.
Future Plans
Characterize abilities of the primary human breast cancer cell lines to grow in the animal model.
4.
Publications
Johnson KJ, Peck AR, Liu C, Tran TH, Utama FE, Sjolund AB, Schaber JD, Witkiewicz AK, Rui H. PTP1B
suppresses prolactin activation of Stat5 in breast cancer cells. Am J Pathol. 2010 Dec;177(6):297183. Epub 2010 Oct 15.
93
Kongming Wu
Assistant Professor
1.
Description of Research: Our previous studies demonstrate that
DACH1 is a potential tumor suppressor by inhibiting human breast cancer
cellular proliferation, invasion and metastasis. Recent studies suggested
that DACH1 block breast cancer stem cell propagation and induce stem
cell differentiation. We will further analyze the molecular mechanism
underlie this new function of DACH1.
2. Current Research Projects: The role of DACH1 in breast cancer
3. Grant Support: Margaret Q. Landenberger Research Foundation
4. Future Plans: The role of RDGN network in cancer initiation and progression
5. Publications:
He Y, Zhao J, Wu D, Wyckhuys KA, Wu K. Sublethal effects of imidacloprid on Bemisia tabaci
(Hemiptera: Aleyrodidae) under laboratory conditions. J Econ Entomol. 2011 Jun;104(3):833-8.
DeAngelis T, Wu K, Pestell R, Baserga R. The type 1 insulin-like growth factor receptor and
resistance to DACH1. Cell Cycle. 2011 Jun 15;10(12):1956-9. Epub 2011 Jun 15.
Liu Z, McNeil JN, Wu K. Flight mill performance of the lacewing Chrysoperla sinica (Neuroptera:
Chrysopidae) as a function of age, temperature, and relative humidity. J Econ Entomol. 2011
Feb;104(1):94-100.
Zhang T, Gu S, Wu K, Zhang Y, Guo Y. Construction and analysis of cDNA libraries from the
antennae of male and female cotton bollworms Helicoverpa armigera (Hübner) and expression
analysis of putative odorant-binding protein genes. Biochem Biophys Res Commun. 2011 Apr
8;407(2):393-9. Epub 2011 Mar 21.
Reduced levels of membrane-bound alkaline phosphatase are common to lepidopteran strains
resistant to Cry toxins from Bacillus thuringiensis. Jurat-Fuentes JL, Karumbaiah L, Jakka SR, Ning
C, Liu C, Wu K, Jackson J, Gould F, Blanco C, Portilla M, Perera O, Adang M. PLoS One. 2011 Mar
1;6(3):e17606.
An J, Gao Y, Wu K, Gould F, Gao J, Shen Z, Lei C. Vip3Aa tolerance response of Helicoverpa
armigera populations from a Cry1Ac cotton planting region. J Econ Entomol. 2010
Dec;103(6):2169-73.
Wu K. No refuge for insect pests. Nat Biotechnol. 2010 Dec;28(12):1273-5. No abstract
available.
Zhou J, Liu Y, Zhang W, Popov VM, Wang M, Pattabiraman N, Suñé C, Cvekl A, Wu K, Jiang J,
Wang C, Pestell RG. Transcription elongation regulator 1 is a co-integrator of the cell fate
determination factor Dachshund homolog 1. J Biol Chem. 2010 Dec 17;285(51):40342-50. Epub
2010 Oct 18.
Wu K, Jiao X, Li Z, Katiyar S, Casimiro MC, Yang W, Zhang Q, Willmarth NE, Chepelev I, Crosariol
M, Wei Z, Hu J, Zhao K, Pestell RG. Cell fate determination factor Dachshund reprograms breast
cancer stem cell function. J Biol Chem. 2011 Jan 21;286(3):2132-42. Epub 2010 Oct 11.
Liu C, Li Y, Gao Y, Ning C, Wu K. Cotton bollworm resistance to Bt transgenic cotton: a case
analysis. Sci China Life Sci. 2010 Aug;53(8):934-41. Epub 2010 Sep 7. Review.
94
Liu C, Gao Y, Ning C, Wu K, Oppert B, Guo Y. Antisera-mediated in vivo reduction of Cry1Ac
toxicity in Helicoverpa armigera. J Insect Physiol. 2010 Jul;56(7):718-24. Epub 2009 Dec 27.
6. Memberships: Active member of American Association of Cancer Research
95
Zuoren Yu
Assistant Professor
1.
Description of Research
miRNA regulation of breast cancer tumorigenesis and metastasis
2.
Current Research Projects
a) miR-17/20 regulation of breast cancer
b) Cyclin D1a, D1b and D1ke transgenic mouse
c) Cyclin D1/Rb regulation of miRNA
3. Future Plans
a) In vivo investigation of miRNA function on breast cancer using mice model.
b) Link miRNA, cancer stem cell to EMT and metastasis of breast cancer.
96