ONCOGENOMICS UNIT
Unit Address
Azienda Ospedaliero-Universitaria Pisana
c/o IFC-CNR
Via Moruzzi 1 - 56124 Pisa
Tel. + 39 050 315 2780
Fax + 39 050 315 3327
e-mail: laura.poliseno@gmail.com
Principal Investigator
Laura Poliseno, PhD
Team Members
Claudia Mattioli, PhD, Post-doctoral Fellow, mattioliclaudia@hotmail.com
Marianna Vitiello, PhD Student, mariannavitiello@live.it
Ilaria Rizzo, Graduate Student, rizzo_ilaria@tiscali.it
Simone Lubrano, Undergraduate Student, lubranosimone@hotmail.com
Elisa Mercoledi’, Undergraduate Student, elisa.mercoledi@hotmail.com
Andrea Tuccoli, PhD, Research Assistant, a.tuccoli@gmail.com
Main research themes
Melanoma is the most dangerous type of
skin cancer, responsible for almost 60% of
the deaths. Each year about 160,000 new
cases are diagnosed worldwide and about
48,000 melanoma-related deaths are
reported. Furthermore, despite efforts to
improve self-awareness and prevention and
contrary to the more common breast, lung,
colorectal and prostate cancer, melanoma
incidence keeps increasing: the 4 to 6%
annual increase shown by melanoma is the
highest among all cancer types and will
cause a doubling of the number of
diagnosed patients every 10-20 years [1].
Melanoma is historically considered one of
the
most
therapeutically
challenging
malignancies. Localized melanoma can be
treated by surgical resection with a cure rate
of 80%, but metastatic melanoma (MM)
patients still have a median overall survival
of only 6-9 months and an extremely poor 5year survival rate (less than 5%) [2]. After
decades of stagnation, anti-MM therapy has
been recently boosted by newly-developed
immunologic and oncogene-targeted drugs,
which have shown better results than
conventional chemotherapy, in terms of both
response rate and progression-free/overall
survival [3-5]. However, currently available
therapeutic regimens are all plagued by the
phenomena of intrinsic and acquired
resistance: not all patients respond to
treatment and those who initially respond will
invariably show signs of progressive disease
within few months [6]. The chemoresistance
Figure 1. Pseudogenes function as competitive endogenous
RNAs (ceRNAs). Representative example of a tumor suppressor
gene (i.e. PTEN) and its highly homologous pseudogene (i.e.
PTENP1) that share microRNA recognition elements (MREs) in
their 3’UTR. The pseudogene, acting as a decoy, sequesters
microRNA molecules away from the coding mRNA, contributing to
its upregulation and hence opposing to tumorigenesis. Image
taken from: http://www.focushms.com/features/old-dog-revealsnew-tricks/
of melanoma cells is at least partially due to their high degree of heterogeneity and plasticity. Current
therapeutic approaches fail to completely eradicate the tumor because they are not able to kill the full spectrum
of malignant cells and allow the expansion of insensitive/resistant sub-populations [7].
microRNAs are short 18-25nt single stranded RNA molecules that act as negative post-transcriptional
regulators of gene expression by binding to partially complementary sites (microRNA recognition elements,
MREs) and causing a decrease in target RNA stability and translation [8]. microRNAs are drivers of human
cancer (the loss of tumor suppressive microRNAs can enhance the expression of target oncogenes, while the
increased expression of oncogenic microRNAs can repress target tumor suppressor genes) and they are
widely used as biomarkers of diagnosis, prognosis and drug resistance [9, 10].
The discovery of a biological function for different classes of long non-coding RNAs, such as large
intergenic non-coding RNAs, natural antisense transcripts and pseudogenes, has contributed to reconcile the
apparent paradox that the vast majority (>90%) of the human genome is translated, while only 1-2% of it
encodes for proteins. Long non-coding RNAs affect the expression of protein-coding genes acting at the
epigenetic, transcriptional or post-transcriptional level. In particular, we have contributed to discover that
pseudogenes act as competitive endogenous RNAs (ceRNAs) that bind to microRNA molecules and sequester
them away from other targets, opposing to microRNA-mediated post-transcriptional regulation [11] (Figure 1).
Long non-coding RNAs are deregulated in human cancer, where they can exert oncogenic and
oncosuppressive activities [12, 13].
The main research themes of the Oncogenomics Unit, which started its research activities in June 2012, are:
1. to improve the management of metastatic melanoma patients by identifying microRNAs associated with
resistance to conventional and targeted therapeutic approaches and by evaluating their ability to predict its
onset and monitor its course.
2. to achieve a deeper understanding of the molecular bases underlying the biological properties of
melanoma cells by annotating the non-coding part of their transcriptome. Both short (microRNAs) and the
different classes of long non-coding RNAs will be identified and their involvement in melanoma genesis,
progression and chemoresistance will be studied.
REFERENCES
1.
Garbe, C. and U. Leiter, Melanoma epidemiology and trends. Clin Dermatol, 2009. 27(1): p. 3-9.
2.
Rubin, K.M. and D.P. Lawrence, Your patient with melanoma: staging, prognosis, and treatment.
Oncology (Williston Park), 2009. 23(8 Suppl): p. 13-21.
3.
Flaherty, K.T., et al., Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med,
2010. 363(9): p. 809-19.
4.
Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J
Med, 2010. 363(8): p. 711-23.
5.
Hauschild, A., et al., Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label,
phase 3 randomised controlled trial. Lancet, 2012.
6.
Ko, J.M. and D.E. Fisher, A new era: melanoma genetics and therapeutics. J Pathol, 2011.
7.
La Porta, C.A., Mechanism of drug sensitivity and resistance in melanoma. Curr Cancer Drug Targets,
2009. 9(3): p. 391-7.
8.
Huntzinger, E. and E. Izaurralde, Gene silencing by microRNAs: contributions of translational
repression and mRNA decay. Nat Rev Genet, 2011. 12(2): p. 99-110.
9.
Lujambio, A. and S.W. Lowe, The microcosmos of cancer. Nature, 2012. 482(7385): p. 347-55.
10.
Cortez, M.A., et al., MicroRNAs in body fluids--the mix of hormones and biomarkers. Nat Rev Clin
Oncol, 2011. 8(8): p. 467-77.
11.
Poliseno, L., et al., A coding-independent function of gene and pseudogene mRNAs regulates tumour
biology. Nature, 2010. 465(7301): p. 1033-8.
12.
Gutschner, T. and S. Diederichs, The Hallmarks of Cancer: A long non-coding RNA point of view. RNA
Biol, 2012. 9(6).
13.
Kalyana-Sundaram, S., et al., Expressed pseudogenes in the transcriptional landscape of human
cancers. Cell, 2012. 149(7): p. 1622-34.
RESEARCH GRANTS
ITT Start-up funding 2012-2015
MAIN COLLABORATIONS
-Other CRL-ITT Units
-Istituto di Fisiologia Clinica, CNR, Pisa,
-Laboratory of Integrative System Medicine, IIT/IFC-CNR, Pisa
-Dipartimento Oncologico, Azienda Ospedaliero Universitaria Pisana
-Department of Dermatology, IMCG, New York University, New York, USA
-Division of Biostatistics, New York University, New York, USA
-Center for Computational Science, University of Miami, Miami, USA
-Department of Medicine and Pathology, BIDMC-Harvard medical School, Boston, USA
PUBLICATIONS
1. Poliseno L., Tuccoli A., Mariani L., Evangelista M., Citti L., Woods K., Mercatanti A., Hammond S. and
Rainaldi G. MicroRNAs modulate the angiogenic properties of HUVECs. Blood. 2006 Nov 1; 108(9):3068-71.
2. Poliseno L., Pitto L., Simili M., Mariani L., Riccardi L., Ciucci A., Rizzo M., Evangelista M., Mercatanti
A.,Pandolfi P.P. and Rainaldi G. The Proto-oncogene LRF is under post-transcriptional control of miR20a:implications for senescence. PLosOne 2008 Jul 2; 3(7):e2542.
3. Maeda T., Ito K., Merghoub T., Poliseno L., Hobbs R.M., Wang G., Dong L., Maeda M., Dore L.C., Zelent
A., Luzzatto L., Teruya-Feldstein J., Weiss M.J. and Pandolfi P.P. LRF is an essential downstream target
ofGATA1 in erythroid development and regulates BIM-dependent apoptosis. Dev Cell. 2009 Oct; 17(4):527-40.
4. Poliseno L., Salmena L., Riccardi L., Fornari A., Sup Song M., Hobbs R.M., Sportoletti P., Varmeh S., Egia
A., Fedele G., Rameh L., Loda M. and Pandolfi P.P. Identification of the miR-106b~25 microRNA cluster as a
proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal.
2010 Apr 13;3(117):ra29.
5. Poliseno L., Salmena L., Zhang J., Carver B., Haveman W.J., and Pandolfi P.P. A coding-independent
function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010 Jun 24;465(7301):1033-8.
6. Rose A.E., Poliseno L., Wang J., Clark M., Pearlman A., Wang G., Vega Y Saenz de Miera E.C.,Medicherla
R., Christos P.J., Shapiro R.L., Pavlick A.C., Darvishian F., Zavadil J., Polsky D., Hernando E., Ostrer H. and
Osman I. Integrative genomics identifies molecular alterations that challenge the linear model ofmelanoma
progression. Cancer Res. 2011 Feb 22.
7. Penna E., Orso F., Cimino D., Tenaglia E., Lembo A., Quaglino E., Poliseno L., Haimovic A., Osella-Abate
S., De Pittà C., Pinatel E., Stadler M.B., Provero P., Bernengo M.G., Osman I. and Taverna D. microRNA-214
contributes to melanoma tumour progression through suppression of TFAP2C. EMBO J. 2011 Apr 5.
8. Salmena L., Poliseno L., Tay Y., Kats L. and Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a
hidden RNA language? Cell. 2011 Aug 5;146(3):353-8.
9. Poliseno L., Haimovic A., Christos P.J., Vega Y Saenz de Miera E.C., Shapiro R., Pavlick A., Berman R.S.,
Darvishian F. and Osman I. Deletion of PTENP1 pseudogene in human melanoma. J Invest Dermatol. 2011
Dec;131(12):2497-500.
10. Huynh C., Poliseno L., Segura M.F., Medicherla R., Haimovic A., Menendez S., Shang S., Pavlick A.,
Shao Y., Darvishian F., Boylan J.F., Osman I. and Hernando E. The novel gamma secretase inhibitor
RO4929097 reduces the tumor initiating potential of melanoma cells. PLoS One. 2011;6(9):e25264.
11. Tay Y., Kats L., Salmena L., Weiss D., Tan S.M., Ala U., Karreth F., Poliseno L., Provero P., Di Cunto F.,
Lieberman J., Rigoutsos I. and Pandolfi P.P. Coding-independent regulation of the tumor suppressor PTEN by
competing endogenous mRNAs. Cell. 2011 Oct 14;147(2):344-57.
12. Poliseno L., Haimovic A., Segura M.F., Hanniford D., Christos P.J., Darvishian F., Wang J., Shapiro R.L.,
Pavlick A.C., Berman R.S., Hernando E., Zavadil J. and Osman I. Histology specific microRNA alterations in
melanoma. J Invest Dermatol. 2012 Jul;132(7):1860-8.
13. Poliseno L. Pseudogenes: newly discovered players in human cancer. Sci Signal. 2012 Sep
18;5(242):re5. PMID: 22990117.
14. Song S.J., Poliseno L., Song M.S., Ala U., Webster K., Ng C., Beringer G., Brikbak N.J., Yuan X., Cantley
L.C., Richardson A.L. and Pandolfi P.P. MicroRNA-Antagonism Regulates Breast Cancer Stemness and
Metastasis via TET-Family-Dependent Chromatin Remodeling. Cell. 2013 Jul 2. doi:pii: S0092-8674(13)007654. 10.1016/j.cell.2013.06.026. [Epub ahead of print]