CNIO
CANCER
CONFERENCES
2008
Development and Cancer
Madrid|4-6 February 2008
Organizers
Konrad Basler
Gines Morata
Eduardo Moreno
Miguel Torres
CNIO
CANCER
CONFERENCES
2008
Development and Cancer
Madrid|4-6 February 2008
Organizers
Konrad Basler, Zurich, Switzerland
Gines Morata, Madrid, Spain
Eduardo Moreno, Madrid, Spain
Miguel Torres, Madrid, Spain
Summary <<
Program Detailed
9
Sessions Abstracts 17
Posters Abstracts 49
Invited Speakers Portfolio 69
List of Invited Speakers and Participants 91
Calendar of CNIO Activities 2008 98
Previous CNIO Cancer Conferences 100
CNIO
CANCER
CONFERENCES
2008
Development and Cancer
Madrid|4-6 February 2008
DETAILED
PROGRAM
CNIO
CANCER
CONFERENCES
10
2008
MONDAY, February 4
Welcome Address
Eduardo Moreno
TUESDAY, February 4
Session 3:
Stem Cells
Chair:
Session 1:
Cell Competition
Chair:
Konrad Basler
09:15|11:00
Takashi Adachi-Yamada
Nicholas E. Baker
Gines Morata
>> Coffee break and poster session
11:30|13:20
Eduardo Moreno
David A. Shafritz
Offer Gerlitz
Tatsushi Igaki
>> Lunch and poster session
Session 2:
Development
and Cancer in Mammals
Chair:
Francesco Blasi
14:30|16:00
Napoleone Ferrara
Luis Parada
Miguel Manzanares
>> Coffee break and poster session
16:30|18:00
Miguel Torres
Gijs R. van den Brink
Erwin Wagner
Program overview
Eduardo Moreno
09:30|11:15
María A. Blasco
Ruth Lehmann
Haifan Lin
>> Group Picture.
Coffee break and poster session
12:00|13:10
Isidro Sánchez-García
Allan Spradling
>> Lunch and poster session
Session 4:
Development
and Cancer in Drosophila
Chair:
Gines Morata
14:30|16:00
Konrad Basler
Duojia Pan
Nicolas Tapón
>> Coffee break and poster session
16:30|18:00
Juergen Knoblich
Iswar Hariharan
Fernando Casares
WEDNESDAY, February 4
Session 5:
Growth Control and Cancer
in Drosophila and Mammals
Chair:
Miguel Torres
09:30|13:00
Georg Halder
María Dominguez
Francesco Blasi
Marco Milán
Stefan Thor
Closing remarks
and Poster Prize
>> Lunch
Development and Cancer
Madrid|4-6 February 2008
11
MONDAY, February 4 <<
Welcome Address
09:00|09:15
Eduardo Moreno
Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
Session 1:
Cell Competition
Chair:
Konrad Basler
Institute of Molecular Biology, Zurich, Switzerland
Takashi Adachi-Yamada
Kobe University, Kobe, Japan
Restoration of abnormal cell population through nonautonomous activation of JNK
Nicholas E. Baker
Albert Einstein College of Medicine, New York, USA
The active role of corpse engulfment pathways during cell competition
Gines Morata
Centro de Biología Molecular “Severo Ochoa” - CBM/CSIC, Madrid, Spain
Cell competition and tumor progression in the Drosophila wing disc
09:15|09:50
09:50|10:25
10:25|11:00
>> Coffee break and poster session
11:00|11:30
Eduardo Moreno
11:30|12:05
Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
Preliminary analysis of a cell competition response in Drosophila
David A. Shafritz
Albert Einstein College of Medicine, New York, USA
Liver Repopulation by fetal liver stem/progenitor cells: convergence between cell competition and liver size control
12:05|12:40
Short talk: Offer Gerlitz
12:40|13:00
Short talk: Tatsushi Igaki
13:00|13:20
>> Lunch and poster session
13:20|14:30
The Hebrew University, Jerusalem, Israel
A novel mechanism spatially regulating cell-competition
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, USA
Intrinsic tumor suppression and epithelial maintenance by cell-cell communications
Program
12
Session 2:
Chair:
CNIO
CANCER
CONFERENCES
2008
Development and Cancer in Mammals
Francesco Blasi
FIRC Institute of Molecular Oncology, Milan, Italy
14:30|15:05
Napoleone Ferrara
Genentech Inc. San Francisco, USA
Targeting VEGF-A to treat cancer and other disorders
15:05|15:40
Luis Parada
15:40|16:00
Short talk: Miguel Manzanares
16:00|16:30
>> Coffee break and poster session
16:30|17:05
Miguel Torres
17:05|17:40
Gijs R. van den Brink
17:40|18:00
Short talk: Erwin Wagner
UT Southwestern Medical Center, Dallas, USA
CNS stem cells and cancer stem cells
Centro Nacional de Investigaciones Cardiovasculares - CNIC, Madrid, Spain
A comparative analysis of embryonic pluripotency and blastocyst lineages
Centro Nacional de Investigaciones Cardiovasculares - CNIC, Madrid, Spain
Cell tracing strategies to understand the development of complex organs and lineages in vertebrates
Leiden University Medical Center, Leiden, The Netherlands
The morphogenetic code and colon cancer development
Research Institute of Molecular Pathology - IMP, Vienna, Austria
Present address:
Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
Role of c-fos in epidermal differentiation and tumor formation
>> TUESDAY, February 5
Session 3:
Chair:
Stem Cells
Eduardo Moreno
Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
09:30|10:05
María A. Blasco
Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
From telomere chromatin to stem cell biology
10:05|10:40
Ruth Lehmann
New York University Medical Center, New York, USA
RNA regulation of stem cell development
Program
Development and Cancer
Madrid|4-6 February 2008
Haifan Lin
University Program in Genetics, Yale University, New Haven, USA
Stem cells, small RNAs, and self-renewal
13
10:40|11:15
>> Group Picture. Coffee break and poster session
11:15|12:00
Isidro Sánchez-García
12:00|12:35
Instituto de Biología Molecular y Celular del Cancer, Salamanca, Spain
Human cancer in the mouse by restricting oncogene expression to the stem cell compartment: implications for
cancer biology and therapy
Allan Spradling
12:35|13:10
Carnegie Institution of Washington, Baltimore, USA
Stem cell competition and its role in the accumulation of pre-cancerous mutations
>> Lunch and poster session
Session 4:
13:10|14:30
Development and Cancer in Drosophila
Chair:
Gines Morata
Centro de Biología Molecular “Severo Ochoa” - CBM/CSIC, Madrid, Spain
Konrad Basler*
14:30|15:05
Institute of Molecular Biology, University of Zurich, Zurich, Switzerland
Development and cancer in Drosophila
Duojia Pan
15:05|15:40
Johns Hopkins University School of Medicine, Baltimore, USA
The Hippo signaling pathway in organ size-control and cancer
Short talk: Nicolas Tapon
15:40|16:00
>> Coffee break and poster session
16:00|16:30
Juergen A. Knoblich
16:30|17:05
Cancer Research UK London Research Institute, London, UK
Src upstream singalling in proliferation and growth control
Institute of Molecular Biotechnology of the Austrian Academy of Sciences - IMBA, Vienna, Austria
Dosophila as a model for stem cell derived tumor formation
Iswar Hariharan
University of California, Berkeley, USA
Regulation of developmental and regenerative growth in Drosophila imaginal discs
Short talk: Fernando Casares
Centro Andaluz de Biología del Desarrollo - CABD/CSIC - UPO, Sevilla, Spain
Homothorax couples the transition from multipotent cells to progenitors with cell cycle regulation during
Drosophila eye development
* Abstract no avaliable
17:05|17:40
17:40|18:00
Program
14
CNIO
CANCER
CONFERENCES
2008
>> WEDNESDAY, February 6
Session 5:
Chair:
Growth Control and Cancer in Drosophila and Mammals
Miguel Torres
Centro Nacional de Investigaciones Cardiovasculares - CNIC, Madrid, Spain
09:30|10:05
Georg Halder
10:05|10:40
María Dominguez
10:40|11:00
Short talk: Francesco Blasi
M.D. Anderson Cancer Cente, Houston, USA
Hippo signaling in growth control in Drosophila
Universidad Miguel Hernandez - CSIC, Alicante, Spain
Notch teams up with the JAK/STAT pathway to promote growth and tumorigenesis
FIRC Institute of Molecular Oncology, Milan, Italy
The Prep1 homeobox gene, role in development and in cancer
11:00|11:20
Short talk: Marco Milán
11:20|11:40
Short talk: Stefan Thor
Institute for Research in Biomedicine - IRB, Barcelona, Spain
A Wingless and Notch double-repression mechanism regulates G1-S transition in the Drosophila wing
Department of Clinical and Experimental Medicine, Linkoping, Sweden
Lineage progression and size in identified Drosophila CNS stem cells
Poster Prize ı
Nature Reviews Cancer sponsors a Prize to the best Poster that consists in an official certificate
and a ONE YEAR subscription to the journal
Closing remarks
>> Lunch
13:00
NOTE:
25-minute
15-minute
discussion: 10-minute after each talk / 5-minute after each short talk
talks:
short talk:
Program
Development and Cancer
Madrid|4-6 February 2008
15
Notes
CNIO
CANCER
CONFERENCES
2008
Development and Cancer
Madrid|4-6 February 2008
sessions
abstracts
18
CNIO
CANCER
CONFERENCES
2008
Restoration of abnormal cell population through
nonautonomous activation of JNK
Takashi Adachi-Yamada, Makoto Umemori, Kousuke Maeda and Masahiko Takemura
Department of
Biology, Graduate
School of Science,
Kobe University,
Kobe, Japan
Cell proliferation, differentiation and apoptosis interact to achieve appropriate development of organs. The
pattern of most developmental processes may be programmed in advance, but accidental or local mistakes in
growth rate and fate decision may also be restored by apoptosis to assure normal development. Using Drosophila
imaginal discs, we have characterized such mechanisms for the restoration of abnormal development.
Decapentaplegic (Dpp), a member of TGF-β superfamily, acts as a morphogen of which a concentration
gradient provides a positional information to the cells in the imaginal discs. When the smooth slope of the
morphogen signaling gradient is distorted by a somatic mosaic with reduced or elevated Dpp signaling, the
mosaic clones undergo apoptosis. At that time, activation of Caspase-3 is observed sporadically both inside
and outside of the clones, whereas activation of JNK is found along the boundary between the clone and
the background cell population, probably in response to cell-cell interactions. This JNK activation has been
proved to help to promote apoptosis.
This nonautonomously-induced apoptosis is not only associated with the aberration of the morphogen activity
gradient, but is also found in abnormal organ identity and overgrowth phenotypes. Thus, the nonautonomous
induction of cell death should be one of the common ways to detect and remove abnormally developing local
cell populations.
Finally, we wondered whether such nonautonomous effects can be applied to other developmental fields,
such as epithelial maintenance of the adult midgut. This should also be achieved by a balance between cell
proliferation, differentiation and apoptosis. In this context, activation of JNK is also effective in restoring
abnormal gut cell proportion but does not induce apoptosis. The restoration in this system may be achieved
by altering cell fate or prolonging longevity of the normally differentiated cells.
Session 1 Chair: Konrad Basler
Cell Competition
Development and Cancer
Madrid|4-6 February 2008
19
The active role of corpse engulfment pathways during cell
competition
Wei Li, Abhijit Kale and Nicholas E. Baker
A lot of proliferation appears quite random during development and it is hard to understand where it is
being regulated. I shall describe some effects of perturbing growth experimentally through genetic mosaics
that contain populations of cells growing differently. A phenomenon called ‘cell competition’ can result. For
example, wild type cells can grow more at the expense of ‘Minute’ cells (cells heterozygous for mutations
in ribosome protein genes); the Minute cells are progressively eliminated. Thus, cell competition results in
reciprocal growth changes in nearby cells. Cell competition suggests a selection for certain types of cells over
others in the construction of tissues (eg wild type cells over ‘Minute’ cells). It turns out that cell competition
is not simply a reflection of defects such as poor survival on the part of the out-competed cells. Rather, outcompeted cells seem to be actively assassinated by the winning cells. This conclusion emerged from studies
of the engulfment of dying, out-competed cells. Mutations in corpse engulfment pathways, which were
expected to reduce the clearance of dead corpses, also reduced the death of ‘Minute’ cells. The requirement
for these genes in the winning cells shows that they are not just bystanders but participate in killing their
neighbors, using genes that have previously been implicated in corpse engulfment. In future, we shall be
studying the seemingly novel apoptosis pathway that cell competition activates in ‘Minute’ cells, and how
this is linked to increased growth and proliferation in the wild type cell population. It will be interesting to
find out whether cell competition occurs in cancer, and whether it can be exploited to manipulate progenitor
cell populations.
Department of
Molecular Genetics,
Albert Einstein College
of Medicine, New
York, USA
Chair: Konrad Basler Session 1
Cell Competition
20
CNIO
CANCER
CONFERENCES
2008
Cell competition and tumour formation in the imaginal discs
Ginés Morata and Ainhoa Pérez-Garijo
Centro de Biología
Molecular “Severo
Ochoa”
CBM - CSIC,
Madrid, Spain
Larvae homozygous for mutations at the tumour suppressor genes of Drosophila lethal giant larvae (lgl),
scribble (scribb) or disc large (dlg) develop extensive neoplastic tumours that affect principally the central
nervous system and the imaginal discs. Thus the lack of any of these products is sufficient to transform
normal imaginal cells into tumorous cells. However, imaginal cells mutant for any of these genes are unable to
develop a tumour if they are surrounded by non-tumour cells. We have been studying the behaviour of clones
of lgl mutant cells in the wing disc to study the interactions between tumour and non-tumour cells. We find
that as a rule lgl clones are eliminated from the wing disc by a process akin to cell competition: they enter
apoptosis mediated by the JNK pathway and the interactions leading to the disappearance of the mutant cells
take place at the border of the clones. We have also found that when these cells contain an additional factor
conferring a high proliferation rate, the lgl mutant cells are transformed into “supercompetitors”, which are
able to eliminate surrounding non-tumour cells and give rise to invasive neoplastic tumours that colonise the
entire disc.
Session 1 Chair: Konrad Basler
Cell Competition
Development and Cancer
Madrid|4-6 February 2008
21
Preliminary analysis of a cell competition response in Drosophila
Eduardo Moreno
Cell competition is an efficient mechanism to ensure that viable but suboptimal cells do not accumulate
within cellular groups, and therefore it is probably linked to the origin of multicellularity (Moreno, Nat. Rev.
Cancer, 2008, in the press). Consistent with this function as a social control that avoids conflicts among cells
within cellular communities, imbalances in cell competition could have a role in the early stages of cancer
formation, when cells start to overrun the social and developmental constraints imposed by the genome.
Cellular Competition
Group, Molecular
Oncology Programme,
Centro Nacional
de Investigaciones
Oncológicas - CNIO,
Madrid, Spain
We consider it is important to note that all genes discovered to date are highly pleiotropic and involved not
only in cell competition, but also in other processes. Therefore, we are not yet able to specifically manipulate
cell competition without affecting other cellular and developmental processes, and it is unclear whether
any cell competition-specific genes actually exist. The field is now faced with the exciting, yet daunting,
challenge of unveiling the molecular instructions, identity and agenda that determine winner cells and loser
cells. For example, are there dedicated components of a “cell competition response”? Among those dedicated
components, are there winner- specific factors and/or loser-specific factors? The discovery of dedicated
components for cell competition could be useful with regard to therapies and/or early detection of tumours.
Using microarray and RNAi screens, we have identified three novel factors that distinguish cell competitionmediated apoptosis from other types of apoptosis. These cell competition specific genes appear to be
functionally conserved in Mammals. The characterization of these factors will be described as well as
the potential implications for cancer. For example, those novel factors might allow us to create targeted
therapies that specifically prevent the apoptosis of surrounding wild-type cells, without preventing tumour-cell
apoptosis, and could serve as markers of cancerization fields, to identify early lesions before morphological
malformations are detectable. Cell competition may also help tumour cells establish themselves in other
tissues during metastasis.
Chair: Konrad Basler Session 1
Cell Competition
22
CNIO
CANCER
CONFERENCES
2008
Liver repopulation by fetal liver stem/progenitor cells:
convergence between cell competition and liver size control
Michael Oertel, Anuradha Menthena, Yuan-Qing Chen, Christoph Koehler, Mariana D. Dabeva
and David A. Shafritz
Marion Bessin Liver
Research Center,
Albert Einstein College
of Medicine,
New York, USA
Several years ago, we discovered that the normal adult liver can be repopulated by transplanted, endodermal
specific, but not lineage committed fetal liver cells, when these cells are transplanted in conjunction with
2/3 partial hepatectomy. However, most of the liver repopulation occurs after the liver regenerates and the
total liver mass remains normal, despite a 23.5% replacement of host hepatocytes by transplanted cells.
Transplanted fetal liver cells differentiate into both mature hepatocytes and bile duct cells, become fully
integrated into the hepatic parenchyma and are indistinguishable from host hepatocytes, except for the
presence of a transplantation marker gene, dipeptidyl peptidase (DPP)IV. Liver repopulation continues to
increase for up to one year, the liver structure is restored, liver repopulation remains essentially constant for
18-24 months (the remaining lifetime of the rat) and liver function is normal. We refer to these cells as fetal
liver stem/progenitor cells (FLSPC).
Rat FLSPC have been cryopreserved and purified to 95% homogeneity, while maintaining full regenerative
capacity. Repopulating FLSPC exhibit increased proliferation compared to host hepatocytes, whereas host
hepatocytes in direct contact or immediately adjacent to transplanted cells show increased apoptosis. Thus,
liver repopulation by transplanted FLSPC in rats is strikingly similar to cell competition, as originally described
during wing development in Drosophila. Interestingly, proliferating transplanted FLSPC and their progeny
show markedly decreased apoptosis, which probably contributes to their high repopulation potential. When
FLSPC are transplanted into 6 or 14 month old rats, repopulation increases progressively and we believe that
there is increased competition between transplanted FLSPC and host hepatocytes in older rats. We believe
that liver repopulation by transplanted FLSPC, increased repopulation by FLSPC in older rats and liver size
control are all mediated by a balance between selected cellular proliferation and apoptosis.
Session 1 Chair: Konrad Basler
Cell Competition
23
Development and Cancer
Madrid|4-6 February 2008
Short Talk
A novel mechanism spatially regulating cell-competition
Yaron Suissa1, Oren Ziv1, Hadar Neuman1, Tama Dinur1, Peter Geuking2, Christa Rhiner3, Marta Portela3,
Fidel Lolo3, Eduardo Moreno3 and Offer Gerlitz1
Cell-competition where under-performing cells are eliminated from a field of normal cells is thought to provide
a general mechanism to avoid developmental misspecification. Recent studies established a ‘survival factorcapture’ model of cell-competition where cells continuously compete for the limited Dpp survival signal.
Thus, cells less efficient at competing for Dpp, upregulate the transcription-repressor Brinker (Brk), thereby
activating apoptosis. We describe here a novel genetic mechanism differentially controlling the spatial cellularresponse to a survival signal within a developing tissue. In a screen for Dpp targets in the developing wing, we
identified a corepressor that interacts with Brk to eliminate cells with reduced Dpp signaling, and is required
for cell-competition. Thus, Dpp regulates the responsiveness to its own survival signal by inversely controlling
the expression of a repressor and its corepressor.
Department of
Biochemistry, Faculty
of Medicine, The
Hebrew University,
Jerusalem, Israel
2.
Institut fur
Molekularbiologie,
Universitat Zurich,
Zurich, Switzerland
3.
Centro Nacional
de Investigaciones
Oncológicas - CNIO,
Madrid, Spain
1.
Chair: Konrad Basler Session 1
Cell Competition
24
Short Talk
CNIO
CANCER
CONFERENCES
2008
Intrinsic tumor suppression and epithelial maintenance by cell-cell
communications
Tatsushi Igaki, Jose Carlos Pastor-Pareja and Tian Xu
Howard Hughes
Medical Institute, Yale
University School of
Medicine,
New Haven, USA
Oncogenic alterations that confer proliferative advantages in epithelial tissues also often trigger apoptosis,
suggesting an evolutionary mechanism by which organisms eliminate aberrant cells from epithelia. However,
the underlying mechanism of how these tissues eliminate oncogenic cells remains to be elucidated. In
Drosophila imaginal epithelia, clones of cells mutant for evolutionarily conserved tumor suppressors, such as
scribble (scrib) or discs large (dlg), lose their epithelial polarity and are eliminated by JNK-dependent cell
death through cell competition. This elimination of mutant cells requires the presence of surrounding wildtype cells, as removing wild-type cells from the mosaic tissue abolishes the elimination. Thus, there may be
cell-cell communications between mutant cells and wild-type cells that regulate the elimination of oncogenic
mutant cells. We found that Eiger, a Drosophila member of the tumor necrosis factor (TNF) superfamily,
functions as a novel tumor suppressor that eliminates oncogenic mutant cells from epithelia. In the absence
of Eiger, these mutant clones are no longer eliminated; instead, they grow aggressively and develop into
tumors. Our data indicate that TNF signaling could be components of an evolutionarily conserved fail-safe
mechanism by which animals maintain epithelial integrity to protect against neoplastic development. The
molecular mechanism by which Eiger eliminates oncogenic mutant cells will be discussed.
Session 1 Chair: Konrad Basler
Cell Competition
Development and Cancer
Madrid|4-6 February 2008
25
Targeting VEGF-A to treat cancer and other disorders
Napoleone Ferrara
Vascular endothelial growth factor (VEGF)-A is a well-characterized angiogenic factor involved in physiological
and pathological growth of blood vessels. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR2) are the main VEGF-A receptors. Loss of a single VEGF-A allele results in defective vascularization and
embryonic lethality. High expression of VEGF-A mRNA has been described in many human tumors. AntiVEGF-A monoclonal antibodies or other VEGF inhibitors block growth and neovascularization in tumor models.
We developed a humanized anti-VEGF-A monoclonal antibody (bevacizumab). Bevacizumab demonstrated
clinical efficacy, including a survival advantage, in multiple tumor types. Bevacizumab has been approved
by the USA Food and Drug Administration (FDA) for the treatment of previously untreated and relapsed
metastatic colorectal cancer and non-small-cell lung cancer, in combination with chemotherapy. Furthermore,
VEGF-A is implicated in intraocular neovascularization associated with active proliferative retinopathies and
the wet form of age-related macular degeneration (AMD). A humanized anti –VEGF-A Fab (ranibizumab) has
been developed for the treatment of the neovascular form of AMD. Ranibizumab administration maintained
and even improved visual acuity and was approved by the FDA for the treatment of AMD in June 2006.
Genentech, Inc, South
San Francisco, USA
Chair: Francesco Blasi Session 2
Development and Cancer in Mammals
26
CNIO
CANCER
CONFERENCES
2008
CNS stem cells and cancer stem cells
Luis F. Parada
University of Texas
Southwestern Medical
Center, Dallas, USA
It is only in the last decade that the existence of self-renewing cells in the brain has become fully appreciated.
As a consequence classic models of gliomagenesis entertained dedifferentiation as a requisite for tumor
initiation. New concepts have arisen with the continuing study of “adult” neural stem cells in vivo and in
vitro. Preparation of neurosphere cultures from primary glioma tissue from human tumors and from mouse
genetic models permits detailed analysis and the hope for a full molecular understanding of these cells and
how they compare to normal stem cells. A central question remains the identification of the cell or tumor
origin. Our own work using tumor suppressor models of gliomagenesis lead us to propose that the cell of
origin in gliomas is an early progenitor cell or possibly the primary stem cell. I will discuss the nature of these
mouse models, recent advances, how we hope to resolve our current working hypothesis, and implications
for sporadic human glioma. If indeed stem or progenitor cells give rise to glioma, it becomes important to
fully understand their properties and physiological roles. We have undertaken such studies in hippocampal
neurogenesis of the mouse.
Session 2 Chair: Francesco Blasi
Development and Cancer in Mammals
27
Development and Cancer
Madrid|4-6 February 2008
Short Talk
A comparative analysis of embryonic pluripotency and blastocyst
lineages
Teresa Rayón, Miguel Crespo, Bárbara Pernaute, Susana Cañón, Beatriz Fernández-Tresguerres,
Eva Alonso and Miguel Manzanares
Morphological evolution proceeds by changing developmental programmes, what results in the appearance of
novel structures and cell populations. The early stages of mammalian development are remarkably different
from other vertebrates, and can be considered in that sense as an evolutionary innovation. The first decision
to occur in the mouse embryo is the specification of the embryonic versus the extraembryonic lineages. This
results in the appearance of different cell populations in the blastocyst, such as the trophobalst and the
epiblast, that are under the control of a specific set of transcription factors including Oct4, Nanog and Cdx2.
Interestingly, these factors are also responsible for the maintenance of pluripotency in stem cells derived
from the blastocyst. We are taking an evolutionary approach in order to understand how this distinguishing
feature of Mammals has arisen, by comparing mouse and chick early embryos and the regulatory networks
involved in these early lineage decisions. At the same time, and by the use of genetic lineage tracing, we are
studying at which point in development are these decision taken, and therefore when does the first restriction
in developmental potential occur.
Department of
Cardiovascular
Developmental
Biology, Centro
Nacional de
Investigaciones
Cardiovasculares
- CNIC, Instituto
de Salud Carlos III,
Madrid, Spain
Chair: Francesco Blasi Session 2
Development and Cancer in Mammals
28
CNIO
CANCER
CONFERENCES
2008
Cell tracing strategies to understand the development of
complex organs and lineages in vertebrates
Cristina Clavería, Carlos G. Arqués, Catiana Rosselló and Miguel Torres
Departamento de
Biología del Desarrollo
Cardiovascular,
Centro Nacional
de Investigaciones
Cardiovasculares
- CNIC, Instituto
de Salud Carlos III,
Madrid, Spain
Definitive hematopoietic stem cells (HSCs) are specified from a specialized endothelial area at the floor of the
embryonic dorsal aorta. Although the molecular and cellular mechanisms involved in this process remain largely
unknown, we have previously shown that the transcription factor Meis1 is required for the generation of HSCs. Meis
genes encode a subfamily of homeodomain transcription factors that regulate the expression of target genes by
binding as cofactors to other transcriptional regulators. Members of this gene family have been assigned important
roles during embryonic patterning of a wide range of animals, from nematodes to Mammals. Overexpression of
the family member Meis1 produces acute myeloid and lymphoblastic leukemia, a function that strictly requires
cooperation with Hox proteins. However, the specific function, regulation, cofactors and target genes of Meis1 during
HSC specification remain unknown.
We report here that Meis1 is expressed in the HSC compartment in the fetal liver and in the primary sites of
definitive hematopoiesis, including the aorta-gonad-mesonephros (AGM) mesenchyme, the hemogenic embryonic
arterial endothelium, and hematopoietic clusters within the aorta and vitelline and umbilical arteries. The HSC
compartments in the fetal liver and AGM of Meis1 mutant mice are severely underdeveloped and their colonyforming potential is profoundly impaired. We have analyzed the putative involvement of Hox genes in this phenotype.
In spite of the implication from in vitro experiments for an involvement of Hox gene function in adult HSC biology,
there is no functional evidence for HSC impairment in Hox mutants. We have examined the expression of the 39
Hox gene mRNAs by in situ hybridization on AGM sections, and find that none is expressed during HSC birth in
the AGM. Our results challenge the view that Hox proteins cooperate with Meis1 during the establishment of the
HSC and thus suggest that the Meis1-activated pathways involved in HSC-specification differ from those that lead
to Meis1-induced leukemias. In contrast to the lack of involvement of Hox genes, a set of transcription factors has
been identified that are specifically expressed in the dorsal aorta HSC clusters: Runx1, c-myb, GATA-2, PU-1, SCL,
Fli1 and Lmo2. These factors may operate as regulators, cofactors or targets of Meis1 activity, and we are currently
using biochemical and functional approaches to define the interactions between these factors and Meis1 during the
establishment of the definitive HSC.
To gain further insight into lineage specification and the cellular events involved in the construction of vertebrate
organs, we have designed new strategies for lineage tracing and clonal analysis that allow detailed investigation
of the clonal composition of vertebrate tissues. We are applying these models in the mouse to determine how cell
proliferation, cell death and cell competition influence normal embryonic development and tissue homeostasis in
the adult.
Session 2 Chair: Francesco Blasi
Development and Cancer in Mammals
Development and Cancer
Madrid|4-6 February 2008
29
The morphogenetic code and colon cancer development
Gijs R van den Brink
The initiating genetic lesion in sporadically occurring cancers is impossible to identify. The existence of rare
inherited cancer syndromes has helped to uncover some of the mutations that can initiate tumorigenesis.
Most of these initiating lesions affect genes belonging to morphogenetic signalling pathways. The speaker
will discuss the evidence that the cellular fate of individual epithelial cells in the adult is nonautonomous
and depends on extrinsic information, just like cells in a developing embryo. Cellular fate in this constantly
regenerating tissue is therefore controlled by the same morphogenetic signalling pathways that shape the
embryo. The speaker will highlight some of the pathways involved in colonic cell fate specification and discuss
how cancer stem cells need to disrupt the extrinsic morphogenetic restraints on unlimited clonal expansion
to gain an autonomous clonal proliferative advantage over neighboring stem cells.
Department of
Gastroenterology and
Hepatology, Leiden
University Medical
Center, Leiden, The
Netherlands
Chair: Francesco Blasi Session 2
Development and Cancer in Mammals
30
Short Talk
CNIO
CANCER
CONFERENCES
2008
Role of c-fos in epidermal differentiation and tumor formation
Juan Guinea-Viniegra1, Rainer Zenz1, Harald Scheuch1 and Erwin F. Wagner1,*
Research Institute of
Molecular Pathology
- IMP, Vienna, Austria
1.
The proto-oncogene c-fos is a major nuclear target for signal transduction pathways involved in the regulation
of cell proliferation, differentiation and transformation. To investigate the function of c-fos in skin development
and skin tumor formation, we generated mice with specific conditional deletion of c-fos in the epidermis. Mice
lacking c-fos in keratinocytes (c-fos∆ep) have no obvious phenotype. In vitro treatment of c-fos∆ep keratinocytes
with increasing concentrations of Ca2+ induced premature differentiation. A similar phenotype was observed
in newborn and adult mice treated topically with TPA. The observed premature and irreversible keratinocyte
differentiation in c-fos∆ep mice is due to increased TACE (TNF-α Converting Enzyme) protein expression,
subsequent Notch1 activation inducing p21 and Caspase 3 expression.
In the context of oncogenic signals driven by H-RasV12, c-fos∆ep keratinocytes expressing Ras exhibit also
premature differentiation. Importantly, tumor-prone K5-SOS transgenic mice lacking c-fos show dramatically
reduced papilloma formation. Detailed molecular analysis revealed that the small tumors consist of highly
differentiated cells; no differences in apoptosis or proliferation were observed. Moreover, conditional and
inducible deletion of c-fos in K5-SOS transgenic mice led to a cessation of tumor growth with the tumors
exhibiting a highly differentiated state. We propose that stress-induced induction of TACE in c-fos deficient
keratinocytes both in vivo and in vitro leads to premature activation of the Notch1 pathway causing increased
differentiation and reduced tumor formation.
* Present Address:
Cancer Cell Biology Programme, Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
Session 2 Chair: Francesco Blasi
Development and Cancer in Mammals
Development and Cancer
Madrid|4-6 February 2008
31
From telomere chromatin to stem cell biology
María A. Blasco, Stefan Schoeftner, Ignacio Flores and Antonia Tomas
Telomeres protect the chromosome ends from unscheduled DNA repair and degradation. Mammalian
telomeres consist of non-coding TTAGGG repeats that are bound by the multi-protein complex “shelterin”,
protecting chromosome ends from DNA repair mechanisms and degradation. We have shown in the past
that mammalian telomeric chromatin is enriched for the constitutive heterochromatin marks H3K9me3,
H4K20me3 and HP1. Similar to pericentric heterochromatin, telomeric heterochromatin is thought to be
fundamental for the maintenance of chromosomal integrity. I will discuss our recent findings that highly
compacted telomeric chromatin structures are transcribed by DNA dependent RNA polymerase II, which is
recruited to telomeres by a TRF1 containing “shelterin” complex. Telomeric RNAs (TelRNAs) contain UUAGGG
repeats, are polyadenylated and transcribed from the telomeric C-rich strand. Transcription of mammalian
telomeres is regulated by several mechanisms including developmental status, telomere length, cellular stress
and chromatin structure. TelRNAs are associated with telomeric chromatin but can also occupy large nuclear
domains suggesting that TelRNAs can spread along a chromatin template. Importantly, we provide evidence
that TelRNAs block the activity of telomerase in vitro suggesting that TelRNAs may regulate telomerase
activity at chromosome ends. These results indicate that TelRNAs are novel components of mammalian
telomeres, which are anticipated to be fundamental for understanding telomere biology and telomere-related
diseases such as cancer and ageing.
Telomeres and
Telomerase Group,
Molecular Oncology
Programme,
Centro Nacional
de Investigaciones
Oncológicas - CNIO,
Madrid, Spain
Finally, I will discuss that telomere length and the catalytic component of telomerase, Tert, are critical
determinants for the mobilization of epidermal stem cells. The effects of telomerase and telomere length
on stem cell behavior anticipate the premature aging and cancer phenotypes of telomerase mutant mice.
Furthermore, we will present recent results showing the importance of telomere length in the biology of stem
cell niches and how we have used this information to generate long-lived mice.
Chair: Eduardo Moreno Session 3
Stem Cells
32
CNIO
CANCER
CONFERENCES
2008
RNA regulation of stem cell development
Ruth Lehmann
HHMI, The Helen L.
and Martin S. Kimmel
Center for Biology
and Medicine at the
Skirball Institute, NYU
School of Medicine,
New York, USA
In most organisms, primordial germ cells (PGCs) are set-aside early during embryogenesis. Subsequently,
PGCs migrate through the embryo, associate with somatic gonadal cells and form the gonad. While PGCs
seem highly specialized, their products are the ultimate stem cells that generate a complete organism
generation after generation. We are interested in how germ line stem cell fate is established in the embryo and
maintained during adult stages. Transcriptional regulation as well as translational control play an important
role in controlling germ cell proliferation and germ line stem cell maintenance. We have used RNA expression
screens to identify genes whose RNAs are specifically present in germ cells. We found that the 3’UTR of these
RNAs instructs the time when the RNAs are translated during germ cell development. This has let to the
identification new targets for the translational regulators Nanos and Pumilio. These targets affect germ cell
transcriptional silencing in primordial germ cells and germ line stem cell proliferation in the adult.
Session 3 Chair: Eduardo Moreno
Stem Cells
Development and Cancer
Madrid|4-6 February 2008
33
Stem cells, small RNAs, and self-renewal
Haifan Lin
The hallmark of stem cells is their ability to self-renew meanwhile capable of producing numerous differentiated
daughter cells. Previously, we identified the Argonuate/Piwi protein family to be essential for stem cell
self-renewal in diverse organisms. This protein family can be divided into Argonuate and PIWI subfamilies.
Recently, we and others discovered that the PIWI subfamily proteins interact with a novel class of noncoding small RNAs that we named PIWI-interacting RNAs (piRNAs)1. There are at least 60,000 species of
piRNAs. They are mostly 26~32 nucleotides in length, and are abundantly expressed during spermatogenesis.
Individual piRNAs frequently correspond to intergenic and repetitive sequences. In addition, a small number
of piRNAs correspond to exonic and intronic sequences. This broad genomic distribution of piRNAs implicates
their potential involvement in diverse mechanisms of gene regulation during spermatogenesis. Our latest work
suggests that PIWI subfamily proteins and specific piRNAs are involved in epigenetic programming as well as
the regulation of mRNA stability and, possibly, translation. Such regulations are involved in controlling the
self-renewing division of germline stem cells and other gametogenic events in Drosophila and Mammals.
1
Yale Stem Cell Center,
Yale University School
of Medicine,
New Haven, USA
Lin, H. (2007) piRNAs in the Germline Science 316: 397.
Chair: Eduardo Moreno Session 3
Stem Cells
34
CNIO
CANCER
CONFERENCES
2008
Human cancer in the mouse by restricting oncogene expression to the
stem cell compartment: implications for cancer biology and therapy
Isidro Sánchez-García
Experimental
Therapeutics and
Translational Oncology
Program, Instituto de
Biología Molecular y
Celular del Cáncer,
CSIC/Universidad
de Salamanca,
Salamanca, Spain
The Cancer Stem Cell (CSC) hypothesis suggests that tumors are hierarchically organized as abnormal tissues
which originate from, and are maintained by, transformed stem cells. This fact would explain the failure of
many anti-cancer strategies. Evidence supporting this model has been generated for several types of human
cancers. To elucidate the contribution that CSCs make to the generation and maintenance of cancer, we
have developed a strategy to limit oncogene expression to the stem cell compartment in a transgenic mouse
setting. In my seminar, I will discuss how oncogene expression in a stem cell is all that is required to fully
reprogram it, giving rise to a full-blown, oncogene-specified tumour with all its mature cellular diversity, and
that elimination of the CSCs is enough to eradicate the whole tumour.
Session 3 Chair: Eduardo Moreno
Stem Cells
Development and Cancer
Madrid|4-6 February 2008
35
Stem cell competition and its role in the accumulation of
pre-cancerous mutations
Todd Nystul, Lucy Morris, Don Fox and Allan Spradling
Adult stem cells hold a special status as the relatively undifferentiated, long-term progenitors of a tissue that
can undergo asymmetric, self-renewing divisions. Although stem cells as a group maintain tissue structure
over the adult lifetime, studies of Drosophila stem cells demonstrate that many individual stem cells are
regularly replaced within their niches by the daughters of neighboring stem cells. Replacement was originally
observed between adjacent stem cells within the germline stem cell niche. To investigate long distance
replacement, we have studied the follicle stem cells (FSCs) in the Drosophila ovary, which generate the
follicular epithelium that surrounds developing ovarian follicles. FSC daughters undergo two patterns of
migration that are important for stem cell replacement. About half of the daughters simply migrate along the
basement membrane toward the posterior, but they alternate with daughters that migrate laterally across the
width of the germarium where they target the opposite FSC niche. The observation of regular, directed interniche movement of undifferentiated stem cell daughters provides a mechanism for stem cell replacement.
Cross-migrating daughters usually fail to take up niche residence, but instead interdigitate with the daughters
of the opposite FSC, continue to divide and contribute to forming the follicular epithelium. Sometimes,
however, they displace the resident FSC, remain in the niche and function as active stem cells. We suggest
that stem cell competition is a common and selectively advantageous adaptation that reduces the chance that
deleterious mutations will be maintained in stem cells and their descendents. However, our studies also show
that mutations can arise that cause mutant stem cells to preferentially replace wild type stem cells. These
“hyper-replacer” mutations may be able to spread from one niche to another until they comprise a substantial
portion of tissue and may represent an important new class of precancerous lesion.
HHMI/Embryology,
Carnegie Institution,
Baltimore, USA
Nystul, T. and Spradling, A.C. (2007). An epithelial niche in the Drosophila ovary undergoes long range stem
cell replacement. Cell Stem Cell 1, 277-285.
Chair: Eduardo Moreno Session 3
Stem Cells
36
CNIO
CANCER
CONFERENCES
2008
The Hippo signaling pathway in organ size-control and cancer
Duojia Pan
Department of
Molecular Biology
and Genetics, Johns
Hopkins University
School of Medicine,
Baltimore, USA
How tissues reach and maintain their correct size is a long-standing puzzle in biology. This question is not only
important from a developmental biology perspective, but also highly relevant to the mechanisms underlying
growth-related human diseases such as cancer. Recent elucidation of the Hippo (Hpo) pathway in Drosophila,
which controls organ size by coordinately regulating cell growth, proliferation and apoptosis, represents a
significant advance in addressing this fundamental question. The core of the Hpo pathway comprises of
several tumor suppressor proteins acting in a kinase cascade. Specifically, the Ste20 family kinase Hpo, in a
complex with Salvador (Sav), phosphorylates and activates the NDR kinase Warts (Wts). Wts, in a complex with
the Mob1-related protein Mats, phosphorylates and inactivates Yorkie (Yki), a transcriptional coactivator that
positively regulates genes required for cell growth, survival and proliferation. Inactivation of Hippo pathway
tumor suppressors, or activation of Yki, the only known oncogene in this pathway, leads to a profound increase
in organ size that is characterized by delayed cell cycle exit and absence of developmentally programmed
cell death.
Recently, we have identified a single phosphorylation site in Yki that mediates the growth-suppressive output
of the Hippo pathway. Hippo-mediated phosphorylation inactivates Yki by excluding it from the nucleus,
whereas loss of Hippo signaling leads to nuclear accumulation and therefore increased Yki activity. Using this
phosphorylation event as pathway readout, we showed that the mammalian homologues of Hpo (MST1/2), Sav
(WW45), Wts (Lats1/2) and Yki (YAP) constitute a kinase cascade similar to its Drosophila counterpart. Using
a conditional YAP transgenic mouse model, we demonstrate that the mammalian Hippo pathway is a potent
regulator of organ size, and that its dysregulation leads to tumorigenesis. Thus, the Hippo pathway represents
a universal size-control mechanism from flies to Mammals.
Session 4 Chair: Gines Morata
Development and Cancer in Drosophila
37
Development and Cancer
Madrid|4-6 February 2008
Short Talk
Src upstream singalling in proliferation and growth control
Paul Langton, Julian Colombani, Birgit Aerne and Nicolas Tapon
Src-family kinases (SFKs) control a variety of biological processes, from cell proliferation and differentiation to
cytoskeletal rearrangements. Abnormal activation of SFKs has been implicated in a wide variety of cancers and
is associated with metastatic behavior. SFKs are maintained in an inactive state by inhibitory phosphorylation
of their C-terminus by Carboxy-terminal Src kinase (Csk). We have identified Drosophila Ankyrin-repeat, SH3domain and Proline-rich-region containing Protein (dASPP) as a new regulator of Drosophila Csk (dCsk)
activity. dASPP is the homolog of the mammalian ASPP proteins, which are known to bind to and stimulate
the pro-apoptotic function of p53. We have shown that dASPP is a positive regulator of dCsk. Firstly, dASPP
loss-of-function causes overgrowth and strongly enhances the specific phenotypes of dCsk mutants in wing
epithelial cells. Secondly, dASPP interacts physically with dCsk to potentiate the inhibitory phosphorylation of
dSrc. Our results suggest a new role for dASPP in maintaining epithelial integrity through dCsk regulation.
Cancer Research UK
London Research
Institute, London, UK
We have also identified Boa as a direct dASPP interactor. boa mutants have a similar overgrowth phenotype
to dASPP mutants and Boa is required for dASPP localization in the apical domain of imaginal disc cells. We
are currently dissecting the role of Boa and dASPP in dCsk activation.
Chair: Gines Morata Session 4
Development and Cancer in Drosophila
38
CNIO
CANCER
CONFERENCES
2008
Drosophila as a model for stem cell derived tumor formation
Juergen A. Knoblich
Institute of Molecular
Biotechnology of the
Austrian Academy
of Sciences - IMBA,
Vienna, Austria
Stem cells can generate self-renewing and differentiating daughter cells at the same time. We are using
Drosophila as a model system to understand, how they control the balance between these two fundamentally
different types of progeny. Using a proteomics approach for proteins that segregate into one of the two
daughter cells in neuroblasts (stem cell like precursors of the central nervous system) we have found the
growth regulator brat (brain tumor). During mitosis, Brat segregates into one of the two daughter cells, where
it downregulates protein synthesis, stops proliferation and prevents cell growth. In brat mutant animals,
all daughter cells of the stem cell undergo self renewal and continue to proliferate. This leads to dramatic
overproliferation and the formation of a stem cell derived tumor which grows indefinitely and kills the animal.
Tumors will continue to proliferate indefinitely, even when transplanted into other flies, thus indicating that
cells become immortalized. Very similar phenotypes are observed in flies mutant for Lethal (2) giant larvae
(Lgl), where Brat is present but does not segregate asymmetrically. Thus, the asymmetric segregation of Brat
into one of the two daughter cells regulates proliferation in Drosophila neural stem cells.
Brat is a member of a conserved protein family charaterized by a similar domain composition. We have
analyzed the function of other family members and find that they regulate self renewal in other types of stem
cells. Like in brat mutants, stem cells overproliferate and form of tissue specific tumors. Our results indicate
that this role might also be conserved in vertebrates suggesting that brat-like proteins have a conserved role
in regulating stem cell self renewal.
Session 4 Chair: Gines Morata
Development and Cancer in Drosophila
Development and Cancer
Madrid|4-6 February 2008
39
Regulation of developmental and regenerative growth
in Drosophila imaginal discs
Iswar Hariharan, Leslie Chen, Michelle Cheng, Abigail Gerhold, Adrian Halme, Yassi Hafezi,
Hiroshi Kanda, Laurence Madden, Alexander Nguyen, Rachel Smith-Bolton and Melanie Worley
In an attempt to identify most of the pathways that regulate tissue growth during normal development, our
laboratory has conducted a genetic screen using FLP-induced mitotic recombination to identify mutations
that result in increased growth in cells of the eye-imaginal disc. We have identified mutations in more than
30 distinct loci and have, so far, identified the relevant transcription unit in 24 of those loci. The majority of
the mutations increase the growth of mutant cells. A minority act in a non-cell-autonomous way to promote
the overgrowth of adjacent wild-type tissue. The identification of these genes has helped us to obtain a more
complete understanding of the regulation of tissue growth in vivo. Also, a subset of these genes is mutated
in human cancers.
Department of
Molecular and Cell
Biology, University of
California, Berkeley,
USA
We are now attempting to understand the mechanisms that regulate regenerative growth in Drosophila
imaginal discs. Classical studies have shown that Drosophila imaginal discs are capable of undergoing
regenerative growth to replace tissue that has been surgically removed. However, these experiments are
difficult and laborious and not easily incorporated into genetic screens. We have developed a new genetic
system that can induce tissue ablation and allow regeneration consistently and efficiently in a large number of
animals. This system uses a Gal4 driver to target imaginal disc tissues, a cell death promoting gene to induce
ablation, and Gal80ts to allow temporal control over ablation and regeneration. We have used this system
to observe changes in the expression levels and patterns of morphogens and growth regulators throughout
the regenerative process. We have also defined a developmental window during which imaginal discs are
competent for regeneration; discs that have aged beyond this window do not regenerate. In addition, we are
screening for mutations and overexpression transgenes that allow regeneration to occur in older discs that are
normally incapable of replacing ablated tissue.
It has also been known for many years that damage to larval tissues elicits a delay in the larva to pupa transition,
which allows damaged tissues to be repaired prior to the onset of metamorphosis. However, the mechanism
by which damaged tissues can modulate the endocrine pathway that triggers the onset of pupariation is not
known. By studying mutations that affect the delay, we have identified components of the pathway that delay
pupariation to accommodate tissue repair.
In summary, our current efforts are aimed at obtaining a detailed understanding of the genetic regulation of
developmental and regenerative growth in Drosophila.
Chair: Gines Morata Session 4
Development and Cancer in Drosophila
40
Short Talk
CNIO
CANCER
CONFERENCES
2008
Homothorax couples the transition from multipotent cells to
progenitors with cell cycle regulation during Drosophila eye development
Carla Lopes and Fernando Casares
Centro Andaluz de
Biología del Desarrollo
CABD/CSIC - UPO,
Sevilla, Spain
During the development of the Drosophila eye, multipotent cells enter a progenitor state before their terminal
differentiation. This multipotent-to-progenitor transition is coupled with a synchronic amplification phase,
known as “first mitotic wave”. After this amplification phase, cells pause their cycle in G1 and become atonalexpressing retinal progenitors. The retinal founder cells, or R8s, are specified among these progenitors. Then,
each R8 nucleates the formation of one ommatidium, or unit eye, by successive recruitment of surrounding
cells. Therefore, the first mitotic wave determines the overall size of the final eye by providing the pool of raw
progenitor among which the R8s will be singled out. The TALE-homeodomain transcription factor homothorax
(hth) has been shown to be necessary to keep the multipotent, proliferative state in the eye primordium,
although the mechanisms through which hth operates are still unknown. Here we investigate how hth and its
control regulate this transition. We show that hth imposes an extended G2 phase in the multipotent cells likely
through the transcriptional down-regulation of string/cdc25, the mitotic trigger. Repression of hth by TGF-b
and hh signals relieves this control, and permits cells to enter mitosis. This entry into mitosis is boosted by a
burst of cdc25/string transcription, which is induced by RDGs and allowed by the absence of hth. With these
results, we propose a model in which hth becomes a central node in the integration of patterning signals and
cell cycle regulators that control the FMW and the acquisition of a G1-arrested progenitor fate.
Session 4 Chair: Gines Morata
Development and Cancer in Drosophila
Development and Cancer
Madrid|4-6 February 2008
41
Hippo signaling in growth control in Drosophila
Georg Halder
The regulation of organ size is fundamental to animal development, yet remarkably little is known about the
mechanisms that control organ size. How do cells know when to stop dividing after an organ has reached
its proper size and how do injured organs regenerate missing or damaged parts? The answers to these
questions are currently unknown, but it is thought that neighboring cells signal to each other to regulate cell
proliferation. However, the nature of these signals and how they regulate organ growth is not known. Through
a genome wide genetic screen in Drosophila, others and us discovered a new signal transduction pathway, the
Hippo pathway, which is essential for the development of properly sized organs. Animals carrying mutations
in Hippo pathway components develop severely overgrown adult structures because cells proliferate beyond
normal organ size, and because cells are resistant to the apoptotic signals that would normally eliminate extra
cells. We have identified several components of the Hippo pathway and a signal transduction pathway from
the plasma membrane to the nucleus has begun to emerge. Most interestingly, we have recently identified
a cell surface receptor that regulates the activity of the Hippo pathway: the atypical Cadherin Fat. We are
currently addressing how the activity of Fat is regulated and what ligands signal through Fat to regulate organ
growth. We are also studying how the Hippo pathway is involved in the regeneration of damaged tissues and
how it regulates cell cycle progression and organ growth.
MD Anderson Cancer
Center, The University
of Texas, Houston,
USA
Chair: Miguel Torres Session 5
Growth Control and Cancer in Drosophila and Mammals
42
CNIO
CANCER
CONFERENCES
2008
Notch teams up with the JAK/STAT pathway to promote growth
and tumorigenesis
María Domínguez1 and Francisco J. Gutierrez-Aviño2
Instituto de
Neurociencias de
Alicante, CSIC - UMH
Alicante, Spain
2.
Institute for Cancer
Genetics, Columbia
University NY, New
York, USA
1.
Cancer is frequently associated with the deregulation of developmental signalling pathways, suggesting
that cancer arises as an alteration/subversion of the developmental programmes controlling normal tissue
organization. Therefore, a better understanding of how developmental pathways govern normal tissue growth
in vivo will help us understand how cancer arises, and how and why specific developmental pathways
cooperate to promote tumorigenesis. In humans, overactivation of the Notch and the JAK/STAT pathways has
independently been implicated in epithelial and blood tumours. In Drosophila, the Notch pathway controls
eye morphogenesis and growth by establishing a conserved dorsal/ventral organizer. I will show that JAK/
STAT signalling is instrumental in the initial establishment of the dorsal/ventral axis, while Notch signalling
subsequently defines the organizer. When forced to act in concert, these pathways promote a robust tumour
phenotype in both epithelial and blood systems. Moreover, I will discuss the basis of oncogenic cooperation
between the JAK/STAT and Notch pathways.
Session 5 Chair: Miguel Torres
Growth Control and Cancer in Drosophila and Mammals
43
Development and Cancer
Madrid|4-6 February 2008
Short Talk
The Prep1 homeobox gene, role in development and in cancer
Francesco Blasi, E. Longobardi and G. Iotti
Prep1 is a homeodomain protein of the MEINOX family (which contains also the Meis sub-family) that
interacts with Pbx1 to regulate transcription. Prep1 has no nuclear localization signal and is carried to the
nucleus by Pbx1. Moreover, neither Prep1 nor Pbx1 bind DNA, but the dimmer has a very high affinity for a
specific sequence. Finally, the Prep1-Pbx1 dimer can bind HoxB1 (and several other Hox proteins) forming a
ternary complex which is required for the expression of at least Hoxb1, Hoxb2, Hoxa2 and Hoxa3. In addition
to Pbx1, Prep1 also binds p160MBP, a nucleolar protein involved in regulating energy metabolism in liver and
muscle. The binding to p160MBP is in alternative to Pbx1, and hence these two proteins inhibit each other.
Prep1 dimerization also increases the half-life of Pbx1 and p160MBP as well as their subcellular localization.
In fact, Prep1 dimerization with Pbx1 hides the nuclear export signal of the latter, while dimerization with
p160MBP displaces the latter from the nucleolus to the nucleoplasm.
FIRC Institute of
Molecular Oncology,
IFOM, Milan, Italy
The Prep1 gene is essential for development (pre-gastrulation embryonic lethality in null mice). Hypomorphic
mice (Prep1i/i) have variable expressivity and mostly die at E17.5 with hemapoietic, ocular and angiogenesis
anomalies. The hematopoietic effect is at the level of the Long Term Repopulating Stem Cells and affects all
lineages, although in the hypomorphic mice the largest effect is visible in the lymphoid sub-population.
A few homozygous hypomorphic embryos survive gestation and live a normal-length life, however with a
series of defects. A very high percentage of adult Prep1i/i mice develop tumors, mostly lymphomas, but
also adenocarcinomas, pheochromocytomas, and others. Tumors can be induced in wild type mice also by
transplantation of the fetal loiver of both heterozuygous and homozygous Prep1i/i mice.
Over 90 human normal tissues and 400 tumors have been tested for expression of Prep1 by both
immunohistochemistry and in situ hybridization (with largely concordant results). Prep1 is expressed in most
tissues. However, a very large proportion of tumors (over 60%, reaching 95% in some tumors) do not express
Prep1.
Chair: Miguel Torres Session 5
Growth Control and Cancer in Drosophila and Mammals
44
Short Talk
CNIO
CANCER
CONFERENCES
2008
A Wingless and Notch double-repression mechanism regulates
G1-S transition in the Drosophila wing
Héctor Herranz1, Francisco A. Martín2 and Marco Milán1
1.
ICREA and
Institute for Research
in Biomedicine,
Barcelona, Spain
2.
Centro de Biología
Molecular “Severo
Ochoa” - CBM/CSIC
- UAM, Madrid, Spain
The control of tissue growth and patterning is orchestrated in various multicellular tissues by the coordinated
activity of the signaling molecules Wnt/Wingless and Notch, and mutations in these pathways can cause
cancer. The role of these molecules in the control of cell proliferation and the crosstalk between their
corresponding pathways remain poorly understood. Crosstalk between Notch and Wingless has been proposed
to organize pattern and growth in the Drosophila wing primordium. Here we report that Wingless and Notch
act in a surprisingly linear pathway to control G1-S progression. We present evidence that these molecules
exert their function by regulating the expression of the dmyc proto-oncogene and the bantam micro-RNA,
which positively modulated the activity of the E2F transcription factor. Our results demonstrate that Notch
acts in this cellular context as a repressor of cell cycle progression and Wingless has a permissive role in
alleviating Notch-mediated repression of G1-S progression in wing cells.
Session 5 Chair: Miguel Torres
Growth Control and Cancer in Drosophila and Mammals
Development and Cancer
Madrid|4-6 February 2008
45
Short Talk
Lineage progression and size in identified Drosophila CNS stem cells
Stefan Thor
The Drosophila central nervous system (CNS) is formed from a set of ~1,000 identifiable stem cells
(neuroblasts), that delaminate from the ectoderm in the early embryo. Due to the segmental and laterally
bisymmetrical nature of the embryo, this complexity can generaly be distilled into a repetitive set ~30
neuroblasts per hemisegment. While it is well established that each neuroblast generates a unique and highly
reproducible lineage of neurons and glia, less emphasis has been placed upon the fact that the lineages
differ drammatically, and reproducibly, in size, from 2 to 40 cells. Since the precise generation of proper
numbers of each cell type is intimitely connected to lineage size, this indicates that cell cycle exit is tigthly
and uniquely controlled in each neuroblast. However, the underlying mechanisms behind these events are
largely unknown.
Department of Clinical
and Experimental
Medicine, Linkoping
University, Linkoping,
Sweden
To address lineage progression and cell cycle controll in the CNS, we are focusing on neuroblast 5-6. We have
mapped the complete composition of this rather large lineage (26 cells), in both the thoracic and abdominal
segments, and have furthermore identified regulators and cell cycle control genes that appear important for
terminating cell division of this neuroblast at the proper stage. We have also conducted a forward genetic
screen for one specific neuron in this lineage, and identified additional regulatory genes as well as cell cycle
determinents that appear to affect lineage size. The implications of these findings for studying Drosophila
CNS development will be discussed.
Chair: Miguel Torres Session 5
Growth Control and Cancer in Drosophila and Mammals
46
Notes
CNIO
CANCER
CONFERENCES
2008
Development and Cancer
Madrid|4-6 February 2008
47
Notes
CNIO
CANCER
CONFERENCES
2008
Development and Cancer
Madrid|4-6 February 2008
posters
abstract
50
CNIO
CANCER
CONFERENCES
2008
1. CDX2 expression is regulated by BMP/SMAD4 pathway
in human gastric carcinoma cell lines
Rita Barros, Bruno Pereira, Maria Azevedo, Isabelle Duluc, Nuno Mendes, Paula Paulo, Filipe Santos-Silva,
Isabelle van Seuningen, Leonor David, Jean-Noel Freund and Raquel Almeida
Institute of Molecular
Pathology and
Immunology of the
University of Porto,
IPATIMUP
Inserm U682,
Strasbourg, France
Medical Faculty of
Porto, Porto, Portugal
Inserm U560, Lille,
France
Poster Session
Intestinal metaplasia (IM) is a preneoplastic lesion induced by CDX2, occurring in the gastric carcinogenesis
pathway usually following Helicobacter pylori (Hp) infection. We hypothesized that the BMP/SMAD4 pathway
might have a role in CDX2 regulation, in this context, for the following reasons: 1. the BMP pathway is
crucial for normal intestinal differentiation and 2. there is an influx of BMP2 and BMP4-producing cells
to the stomach upon Hp infection. To test this hypothesis, we evaluated the expression of key elements
of the BMP pathway in human stomach specimens with IM. Growth factor treatments, with BMP2 and
BMP4, were performed in cultured cells and a knock-down experiment of SMAD4 was done using RNAi. We
observed overexpression of BMPR1A and SMAD4 in 56% of IM foci and pSMAD1/5/8 in 100% of IM foci as
compared to adjacent mucosa. In vitro, treatment of AGS cells with BMP2 and BMP4 increased endogenous
CDX2 expression as well as the intestinal differentiation markers MUC2 and LI-Cadherin. On the other hand,
SMAD4 knock-down led to decreased endogenous CDX2, MUC2 and LI-Cadherin in AGS. Treatment of the
SMAD4 knock-down cells had no influence on CDX2 expression as opposed to wild type cells. A 9.3 Kb
CDX2 promoter could be transactivated by SMAD4 and SMAD1 in a cell-dependent manner. In conclusion,
we identified that the BMP pathway is active in IM and that BMP2 and BMP4 regulate CDX2 expression and
promote intestinal differentiation through the canonical signal transducers.
Development and Cancer
Madrid|4-6 February 2008
51
2. AP-1(Fos/Jun) tetON mice: a novel tool to investigate
the specific functions of a transcription factor complex
Latifa Bakiri1,*, Lionel Gresh1, Aline Bozec1, Maria Helena Idarraga1, Vukoslav Komnenovic1
and Erwin F. Wagner1,*
Manipulation of the mouse genome to generate gain- or loss-of function mice has provided powerful tools
for understanding the molecular processes governing development and pathogenesis. We were able to
demonstrate that the proto-oncogene c-Fos, a component of the dimeric AP-1 transcription factor, is essential
for skeletogenesis. Mice lacking c-Fos develop osteopetrosis due to failure in osteoclast differentiation
(1), while mice overexpressing c-Fos develop osteosarcomas due to osteoblast transformation (2).
To better analyze the specific functions of AP-1 dimers and subunits in vivo, we have utilized a
recombinase-mediated single-copy transgene integration strategy (3). This strategy allows the rapid
and efficient establishment of embryonic stem (ES) cell and mice carrying tetracycline-inducible
genes targeted to a unique locus. We generated a collection of ES cell lines carrying either single AP-1proteins such as c-Fos, Jun or Fra-2 or synthetic AP-1 forced dimers (4) such as cJun~c-Fos, c-Jun~Fra2 and c-Jun~c-Jun, all targeted to the identical tetracycline-controlled genomic locus (tetON cells).
Our initial results show that over-expression of c-Fos in many tissues using a tetracycline activator
expressed from the Rosa26 locus causes lethality in adult mice within two weeks with a dramatic
increase in bone density. Skin lesions are also observed at later time points. Mechanistically, osteoblastspecific gene expression is increased, while serum levels of the osteoclast inhibitor osteoprotegerin are
elevated. We are currently crossing the Fos tetON mice to tissue-specific tetracycline activator mouse lines
to further characterize the phenotype and are also investigating the role of forced AP-1 dimers in vivo.
Research Institute of
Molecular Pathology
- IMP, Vienna, Austria
1.
* Present Address:
Cancer Cell Biology Programme, Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
1. Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, Wagner EF. 1994. c-Fos: a key regulator of
osteoclast-macrophage lineage determination and bone remodeling. Science 266 (5184):443-8.
2.Grigoriadis AE, Schellander K, Wang ZQ, Wagner EF. 1993. Osteoblasts are target cells for transformation in c-fos
transgenic mice. J.Cell. Biol.122 (3):685-701.
3. Beard C, Hochedlinger K, Plath K, Wutz A, Jaenisch R. 2006. Efficient method to generate single-copy transgenic mice
by site-specific integration in embryonic stem cells. Genesis 44(1):23-8.
4. Bakiri L, Matsuo K, Wisniewska M, Wagner EF, Yaniv M. 2002. Promoter specificity and biological activity of tethered
AP-1 dimers. Mol Cell Biol. 22(13):4952-64.
Poster Session
52
CNIO
CANCER
CONFERENCES
2008
3. Does the phenomenon of cell competition exist in Mammals?
Cristina Clavería and Miguel Torres
Department of
Cardiovascular
Developmental
Biology, Centro
Nacional de
Investigaciones
Cardiovasculares CNIC, Madrid, Spain
Poster Session
During development, when cell populations with different growth rates are apposed, faster-growing
cells expand and eliminate slower-growing cells by apoptosis, ultimately giving rise to a normal-sized
organ. This phenomenon, termed “cell competition”, was first described in Drosophila using Minute,
a mutation in a gene encoding a ribosomal protein that results in defective protein synthesis and
slow growth (Morata and Ripoll, 1975). Drosophila myc (dmyc) was recently reported to regulate organ
size by inducing cell competition. Cells with higher Myc levels proliferate more rapidly and eliminate
cells with lower Myc levels by apoptosis, resulting in correct wing size. In addition to its role in normal
development of multicellular organisms, cell competition might also provide a mechanism for the
initiation of tumor formation. Myc is overexpressed in many human cancers, and might allow cells to
become tumorigenic by rapidly overpopulating a tissue while they acquire secondary oncogenic lesions.
Despite the putative importance of cell competition in physiological and pathological processes, its existence
has not been confirmed in vertebrates. To determine whether the cell competition phenomenon is found
in Mammals, and whether it is myc-regulated, we have generated conditional c-Myc-overexpressing clones
in the mouse, using a tamoxifen-inducible Cre recombinase. To characterize the apoptosis intrinsic to this
phenomenon, these clones are combined with non-overlapping clones overexpressing the anti-apoptotic protein
p35. Each clone is labeled with a different fluorescent protein to facilitate detection. We are analyzing the
behavior of these clones, their interactions, and their interaction with wild type cells, as well as organ size, in
transgenic mice. We hope to establish the existence and study the regulation of cell competition in Mammals,
which could provide the basis for understanding its possible implication in development and cancer.
Development and Cancer
Madrid|4-6 February 2008
53
4. A Wingless and Notch double-repression mechanism regulates G1-S transition in the Drosophila wing
Héctor Herranz1, Francisco A. Martín2 and Marco Milán1,3
The control of tissue growth and patterning is orchestrated in various multicellular tissues by the coordinated
activity of the signaling molecules Wnt/Wingless and Notch, and mutations in these pathways can cause
cancer. The role of these molecules in the control of cell proliferation and the crosstalk between their
corresponding pathways remain poorly understood. Crosstalk between Notch and Wingless has been proposed
to organize pattern and growth in the Drosophila wing primordium. Here we report that Wingless and Notch
act in a surprisingly linear pathway to control G1-S progression. We present evidence that these molecules
exert their function by regulating the expression of the dmyc proto-oncogene and the bantam micro-RNA,
which positively modulated the activity of the E2F transcription factor. Our results demonstrate that Notch
acts in this cellular context as a repressor of cell cycle progression and Wingless has a permissive role in
alleviating Notch-mediated repression of G1-S progression in wing cells.
Institute for Research
in Biomedicine - IRB,
Parc Científic de
Barcelona,
Barcelona, Spain
2.
Centro de Biologia
Molecular “Severo
Ochoa” - CBM/CSIC
- UAM, Madrid, Spain
3.
Institució Catalana
de Recerca i Estudis
Avançats - ICREA,
Barcelona, Spain
1.
Poster Session
54
CNIO
CANCER
CONFERENCES
2008
5. Capping Proteins prevent aberrant neoplastic growth of wing
blade epithelium cells
S. Rebelo, Beatriz García Fernández and Florence Janody
Instituto Gulbenkian
de Ciência, Oeiras,
Portugal
The actin cytoskeleton has a central role in controlling cell shape and mobility. In epithelia, a circumferential
band of actin filaments provides the structural support for cell-cell junctions. When the strength of the
epithelial sheet is compromised, cells may undergo epithelium to mesenchymal transition, escape sizecontrol mechanisms, evade cell death and finally acquire the ability to migrate. These features recapitulate
all of the hallmarks that characterize cancer malignancy. Interestingly, clones of cells mutant for either
subunits of the capping protein αβ heterodimer (CP), induced in a heterozygous wild-type background,
are extruded from the wing blade epithelium and died. However, depleting the β subunit (cpb) by RNA
interference (RNAi) in the whole blade leads to a different outcome: epithelium polarity is strongly affected,
few apoptotic cells can be observed, while many seem to overproliferate. This differential behaviour is
unlikely to be due to a dosage effect since RNAi induced-cpb depletion in restricted wing blade domains
also induces cell extrusion and death. This suggests that CP prevent tumorigenesis of wing blade cells.
However, when CP mutant cells are adjacent to wild-type wing blade neighbouring cells, the latest
eliminate mutant cells by a process of cell competition. Consistent to a requirement for CP to prevent
tumorigenesis, expressing the RasV12 oncogene results in neoplastic overgrowths of CP mutant clones.
Highly conserved homologs of CP are found in nearly all eukaryotic cells. CP heterodimer caps actin filament
barded ends, thereby preventing the addition or loss of actin subunits. We found that an HA-tagged form of
Cpa, which could rescue extrusion of cpa mutant cells, co-localizes with components of epithelial junctions
and prevents Armadillo (Arm) and E-Cadherin (E-Cad) mislocalization to basolateral positions in the wing blade
epithelium. Since cellular junctions are critical for maintaining the strength of epithelial sheets and provide
docking sites for a large number of signaling molecules. The role of CP might be to link actin filaments to the
membrane, thereby maintaining the localization of AJ components and preventing aberrant neoplastic growths.
Interestingly, the tumor suppressor function of CP appears to be tissue specific since the above cell behaviour
is only observed in restricted epithelia, including the wing blade and the ovarium follicle epithelium. This
suggests that each epithelium has specific cytoskeleton and/or junctional properties, making cells sensitive
or not to mutations that cause abnormal tumor growth. Altogether our data highlights the crucial impact of
tissue context for the activation of a tumoral process.
Poster Session
Development and Cancer
Madrid|4-6 February 2008
55
6. p73 locus is a positive regulator of the neural stem cells
proliferation and self-renewal
Marta Herreros-Villanueva1, Laura Gonzalez -Cano1, Margarita Marqués1, Gundela Meyer2, Augusto Silva3
and Carmen Marín1*
The p73 gene locus has a “two genes in one” structure that parallels its bi-modal function. Examination
of the p73-/- mice presented multiple neurological abnormalities including enlarged ventricles,
hippocampal dysgenesis, and loss of peripheral sympathetic neurons and reduced cerebral cortex
indicating the relevance of p73 function in neural development. While the role of p73 in the induction
of neuronal differentiation in vitro has been well established (De Laurenzi et al., 2000, Fernández
et al 2007) , its function in the biology of the neural stem cells lineage have never been study.
To address this question we first analyzed the neurogenic niche in the lateral ventricle wall in postnatal p73-/and wt mice. We observed that p73 and p53 are expressed in distinct, partially overlapping cell populations
of the ependyma and in the subependymal neurogenetic niche of the lateral ventricle. Furthermore, in p73-/mice, there is a decrease in the proliferating PCNA positive cells, pointing to an alteration in the neural stem
niche of these animals. Since multipotent self-renewing NSC can be propagated in vitro as neurospheres, we
asked whether the decreased proliferation in the SVZ of the p73-/- mice was accompanied by an alteration in
the number of neurospheres forming cells. Indeed, a decrease in number and size of the neurospheres that
can be cultured from the rostral telencephalon of p73-deficient mouse embryos, compared to wild-type was
observed. To determine if the self-renewal potential of the NSC was affected by the lack of p73, we examined
the relative frequency of neurospheres cells that were capable of reinitiating a clone, and the size of them
during successive passages. We found that not only the neurospheres formed were smaller, but the proportion
of the cells capable of forming neurospheres was significantly lower in the p73-/- neurospheres compared with
WT. To address if the lack of p73 affected NSC self-renewal by deregulating NSC differentiation we analyze
the multipotenciality of the neurosperes. We observed that neurospheres from p73-/- can generate all major
neural cell fates suggesting that the lack of p73 does not affect multipotenciality. However, we detect a
smaller proportion of cells capable of differentiation /neurosphere in the p73-/- when compared with control.
Altogether, this data indicates that p73 is a positive regulator of the neural stem cells proliferation and selfrenewal.
Instituto
Biomedicina,
Universidad de Leon,
Leon, Spain
2.
Dept Anatomia,
Facultad de Medicina,
Universidad de La
Laguna, Santa Cruz
de Tenerife, Spain
3.
Centro de
Investigaciones
Biológicas - CIB/CSIC,
Madrid, Spain
1.
1*
corresponding
Poster Session
56
CNIO
CANCER
CONFERENCES
2008
7. eyeless: a Pax-6 transcription factor linking neurogenesis
and migration in the Drosophila optic lobe
Javier Morante and Claude Desplan
Center for
Developmental
Genetics, Department
of Biology, New York
University, New York,
USA
Poster Session
eyeless, a member of the Pax6 family, is considered as the master control gene for eye development. We report
a new function for Pax6 in regulating the number of neuroblasts in the Drosophila optic lobe. Loss of eyeless
specifically in the optic lobe causes an overgrowth phenotype as a result of an increase in the number of
neuroblasts: neurons accumulate as clusters that form axonal fascicles. Interestingly, this overgrowth is coupled
with the lack of lateral migration that normally happens during pupation and allows neurons to reach their
retinotopic position in the adult optic lobe. Thus, eyeless links neurogenesis and migration in the optic lobe.
Development and Cancer
Madrid|4-6 February 2008
57
8. In vivo regulation of Yorkie phosphorylation and localization
Hyangyee Oh and Ken Irvine
Yorkie, a transcription factor of the Fat and Hippo signaling pathways, is negatively regulated by the
Warts kinase. We characterized Warts-dependent phosphorylation of Yorkie in vivo, and show that
Warts promotes phosphorylation of Yorkie at multiple sites. We also show that Warts inhibits Yorkie
nuclear localization in vivo, and can promote binding of Yorkie to 14-3-3 proteins in cultured cells.
In vivo assessment of the influence of individual upstream regulators of Warts reveals that some
mutants (e.g. fat ) have only partial effects on Yorkie phosphorylation, and weak effects on Yorkie localization,
whereas other genotypes (e.g. ex fat double mutants) have stronger effects on both Yki phosphorylation
and localization. We also identify Serine 168 as a critical site through which negative regulation of Yorkie
by Warts-mediated phosphorylation occurs, but find that this site is not sufficient to explain effects
of Hippo signaling on Yki in vivo. These results identify modulation of subcellular localization as a
mechanism of Yorkie regulation, and establish that this regulation occurs in vivo through multiple sites of
Warts-dependent phosphorylation on Yorkie.
Howard Hughes
Medical Institute,
Waksman Institute
and Department of
Molecular Biology and
Biochemistry, Rutgers
The State University
of New Jersey,
Piscataway, USA
Poster Session
58
CNIO
CANCER
CONFERENCES
2008
9. Enrichment of highly proliferative fetal liver stem/progenitor cells
containing all the repopulation potential of the normal rat liver
Michael Oertel1, Anuradha Menthena1, Yuan-Qing Chen1, Børge Teisner2, Charlotte Harken Jensen2
and David A. Shafritz1
Marion Bessin Liver
Research Center,
Albert Einstein College
of Medicine of Yeshiva
University,
New York, USA
2.
University of
Southern Denmark,
Odense C, Denmark
1.
Previously, we reported long-term liver replacement of normal adult rat liver after transplanting unfractionated
embryonic day (ED)14 fetal liver cells. We showed that fetal liver stem/progenitor cells (FLSPC) proliferate
and differentiate into hepatocytes and mature bile ducts after cell transplantation. Repopulation occurs by
cell competition in which more highly proliferative transplanted FLSPC progressively replace less proliferative
neighboring host hepatocytes by inducing their apoptosis in a mechanism remarkably similar to that described
during Drosophila wing development. The ultimate goal of our research is to discover the molecular basis
for the competitive advantage of FLSPC vs. adult hepatocytes. However, the majority of unfractionated
ED14 fetal liver cells are hematopoietic stem cells (>80%) and <5% are FLSPC. Moreover, purification and
characterization of FLSPC has been problematic, because there are no known specific surface markers for
these cells.
Dlk-1, a cell surface transmembrane protein, is highly expressed in rodent and human fetal liver. We purified
ED14 FLSPC to 95% homogeneity for Dlk-1, using magnetic microbeads (MACS). Dlk-1+ cells are comprised
of a mixture of AFP+/CK-19+ and AFP+/CK-19¯ cells (α-fetoprotein is an hepatocytic marker; cytokeratin-19
is a bile duct epithelial cell marker). Dlk-1+ cells show active proliferation in culture by expressing nuclear
Ki-67, 55.0±1.7% on day 2 and 19.7±3.2% on day 5 after cell plating, and exhibit all the cell culture and
gene expression characteristics expected for hepatic stem/progenitor cells.
After transplantation of Dlk-1+ cells into the normal liver in conjunction with 2/3 partial hepatectomy, these
cells engraft, proliferate, and differentiate into hepatocytes and bile ducts, expressing unique hepatocyteor cholangiocyte-specific proteins (e.g., albumin, G6P, ASGPR and UGT1A1 for hepatocytes and CK-19,
OV-6 and connexin 43 for cholangiocytes). The level of liver repopulation exceeded 15% at 6 months after
transplanting 1.9x106 Dlk-1 purified FLSPC. Since hematopoietic stem cells were totally removed by Dlk1 selection and Dlk-1¯ cells did not repopulate the normal liver, this is the first study to isolate and purify
hepatic stem/progenitor cells that exhibit all of the normal liver repopulation potential found in the fetal liver.
Using Dlk-1 selection to isolate FLSPC and further characterize their gene expression profile, we hope to
identify the specific genes that lead to their competitive advantage vs. adult hepatocytes in repopulating the
normal adult liver.
Poster Session
Development and Cancer
Madrid|4-6 February 2008
59
10. A Myc–Groucho complex integrates EGF and Notch signaling to
regulate neural development
Mona Abed1, Jeffrey Delrow2, Alicia Rosales-Nieves2, David Metzger2, Ze’ev Paroush3,
Robert Eisenman2, Susan M. Parkhurst2 and Amir Orian1
Integration of patterning cues via transcriptional networks to coordinate gene expression is critical during
morphogenesis and is mis-regulated in cancer. Using DamID chromatin profiling (1,2), we identified a proteinprotein interaction between the Drosophila Myc oncogene and the Groucho co-repressor that regulates a subset
of direct dMyc targets. Most of these shared targets affect fate or mitosis particularly during neurogenesis,
suggesting that the dMyc–Groucho may coordinate fate acquisition with mitotic capacity during development.
We find an antagonistic relationship between dMyc and Groucho that mimics the antagonistic interactions
found for EGF and Notch signaling: dMyc is required to specify neuronal fate and enhance neuroblast mitosis,
whereas Groucho is required to maintain epithelial fate and inhibit mitosis. Our results suggest that the
dMyc–Groucho complex defines a novel mechanism of Myc function, and may serve as the transcriptional unit
that integrates EGF and Notch inputs to regulate early neuronal development (3). In addition, the relevance
of our findings to mammalian cancer cell biology will be discussed.
The Rappaport
Faculty of Medicine
and Research
Institute, TechnionIsrael Institute of
Technology, Haifa
Israel
2.
Fred Hutchinson
Cancer Research
Center, Seattle, USA
3.
Department of
Biochemistry, Faculty
of Medicine, The
Hebrew University,
Jerusalem, Israel
1.
Poster Session
60
CNIO
CANCER
CONFERENCES
2008
11. An evolutionarily conserved domain of roX2 RNA is sufficient for
induction of H4-lys16 acetylation on the Drosophila X chromosome
Seung-Won Park, Hyangyee Oh and Yongkyu Park
University of Medicine
and Dentistry of New
Jersey - UMDNJ,
New Jersey Medical
School, Newark, USA
Poster Session
Epigenetic changes of chromatin organization observed in tumor cells have begun to explain human cancer
as an epigenetic disease, not simply a genetic disease, involving DNA methylation and histone modification,
followed by changes in transcriptional expression of cancer-related genes. To study these epigenetic
transcriptional changes, dosage compensation of the male X chromosome in D. melanogaster is an excellent
model system in that 1) MSL (Male-Specific Lethal) complex binds to hundreds of unrelated genes on the
X, and 2) global 2-fold hypertranscription of the X is achieved by epigenetic changes of histone H4-Lys16
acetylation for which two noncoding RNAs, roX1 and roX2 (RNA on X), are required. To characterize the role
of roX RNAs in this process, we have identified evolutionarily conserved functional domains of roX RNAs in
several Drosophila species (eight for roX1 and nine for roX2). Despite low homology between them, malespecific expression and X chromosome specific binding are conserved. Within roX RNAs of all Drosophila
species, we found conserved primary sequences, such as GUUNUACG, in the 3’ end of both roX1 (3 repeats)
and roX2 (2 repeats). A predicted stem-loop structure of roX2 RNA contains this sequence in the 3’ stem
region. Interestingly, the deletion of this stem-loop from roX2 RNA resulted in defective H4-lys16-acetylation
activity on the X chromosome even in the presence of a whole set of MSL proteins on the X chromosome. In
addition, a six tandem repeats of this stem-loop region (72 nt) of roX2 was enough for targeting MSL complex
and inducing H4-Lys16 acetylation on the X chromosome without other parts of roX2 RNA, suggesting that
roX RNAs might play important roles in regulating enzyme activity of MSL complex.
Development and Cancer
Madrid|4-6 February 2008
61
12. Immune response to tumors in Drosophila
José C. Pastor-Pareja, Ming Wu and Tian Xu
We use Drosophila to study basic cancer biology. In our laboratory, several genome-wide screens for mutations
that promote tumor progression and metastasis have been performed. Fly tumors mutant for the polarity
determinant scribble simultaneously expressing an oncogenic form of Ras (RasV12/scrib-/-) exhibit malignant
behavior similar to that observed in human metastatic cancers. Features of these tumors include accelerated
growth, loss of cell adhesion, basement membrane degradation, migration and invasion, as well as secondary
tumor formation. Recently, we have discovered that flies mount an immune response to these tumors. We
are investigating this response and have found that tumors activate blood cells. Blood cells, in turn, adhere
to tumors and affect their growth. We are currently adressing the mechanisms underlying these phenomena
and will present our initial findings regarding signaling and recognition between tumors and immune cells.
This Drosophila model provides a system for dissecting the genetic, molecular and cellular mechanisms of
tumor-immune system interactions.
Howard Hughes
Medical Institute,
Department of
Genetics, Yale
University School of
Medicine,
New Haven, USA
Poster Session
62
CNIO
CANCER
CONFERENCES
2008
13. Ecological interactions within a Drosophila stem cell niche
Christa Rhiner, Begoña Díaz, Marta Portela, Offer Gerlitz, Irene Fernández- Ruiz, Jesús M. López-Gay
and Eduardo Moreno
Cellular Competition,
Group Molecular
Oncology Programme,
Centro Nacional
de Investigaciones
Oncológicas - CNIO,
Madrid, Spain
Poster Session
Stem cells are maintained throughout adult life and accumulate mutations over time affecting their fitness1.
Furthermore, long-lived adult stem cells are also at risk to acquire cancer-promoting mutations1. Because
stem cells are often grouped together within a niche, optimal, suboptimal or harmful stem cells may therefore
coexist and interact. We mimicked such situations using as a model the Drosophila ovary germline stem
cell niche. First, we observed that when suboptimal and normal stem cells coexisted, the faulty cells were
recognized and forced to differentiate. Next, we show that cancerous stem cells can expand not only by
increasing the total amount of stem cells, but also by replacing normal stem cells without changing total
stem cell numbers. Finally, after asymmetric cell division, the mother forces the daughter cell to differentiate,
through competition for a stem cell maintenance factor (BMP/Dpp). Overall, we demonstrate that ecological
interactions within the niche are more important than previously recognized and relevant for normal
homeostasis and disease.
Development and Cancer
Madrid|4-6 February 2008
63
14. Regulation of beta catenin signaling and cell differentiation in
colon carcinoma cells by the Src-family kinase c-Yes
Florence Sancier, Aurélie Telliez, Ludmilla Paquay de Plater, Thomas Edmonds, Géraldine David,
Michel Jan, Muriel Bernigole, Belinda Noël, Nolwen Stéphan-Guigal, Jean-Pierre Galizzi*,
Catherine de Montrion*, Jérôme Dupuis*, Grégory Leclerc*, Francis Cogé, Jean Boutin,
Stéphanie Giraudet, Stéphane Léonce, Michael Burbridge, Alain Bruno, Brian Lockhart*
and Francisco Cruzalegui
c-Yes, a member of the Src family of tyrosine kinases, is found over-activated in colon carcinoma and melanoma.
The specific cellular functions of c-Yes are not clearly elucidated in great part due to the abundance of cSrc activity in most cancers. Here we show that, in HT-29 colon carcinoma cells, stable shRNA-mediated
c-Yes silencing results in an increase in the amounts of E-cadherin at the cell membrane and sequestration
of b-catenin pools at adhesion complexes with concomitant two-to three-fold reduction in the expression of
b-catenin target genes VEGF-A, CD44 and EphB3. These effects on b-catenin signaling are accompanied
by a four-fold increase in apoptosis and a reduction in growth in soft-agar, not observed following c-Src
knock-down. Consistent with a loss of mesenchymal character and a gain of epidermal properties, c-Yes
depleted-HT-29 cells show increased expression of colonic epithelial markers Hath1 and MUC2, normally
repressed by Wnt and Notch signaling. Furthermore, expression of ALDH1, a protein associated to tumour
stem cells, was depressed both at the RNA and protein level. Consistent with reduced mesenchymal and
invasive characteristics, c-Yes-depleted cells failed to generate liver metastases 25 days after intrasplenic
injection in mice. In a subcutaneous growth assay and, contrary to control HT-29 cells, c-Yes knock-down
cells failed to grow into tumours and instead developed small masses rich in mouse stroma. Our in vitro and
in vivo data strongly suggest that deregulated c-Yes activity plays a selective and important role in colon
carcinoma by inhibiting differentiation via the b-catenin pathway.
Divisions of Cancer
Research and Drug
Discovery, Molecular
Pharmacology and
Pathophysiology* and
Molecular and Cellular
Pharmacology,
Croissy Sur Seine,
France
Poster Session
64
CNIO
CANCER
CONFERENCES
2008
15. Sds22, a PP1 phosphatase regulatory subunit, regulates
epithelial cell polarity and shape
Felix A. Grusche, Cristina Hidalgo, Georgina Fletcher, Erik Sahai and Barry J. Thompson
Cancer Research UK
London Research
Institute, London, UK
Poster Session
In a screen for genes regulating epithelial morphology in Drosophila, we identified sds22, a conserved gene
previously characterised in yeast. In the columnar epithelia of imaginal discs, mutation of sds22 causes
contraction of cells along their apical-basal axis, resulting in a more cuboidal morphology. Subsequently,
the sds22 mutant cells lose polarity, leave the epithelium and undergo apoptosis. Similar effects on cell
shape and polarity were observed in the follicle cell epithelium of egg chambers. In yeast, sds22 encodes
a PP1 phosphatase regulatory subunit. Consistent with this, we show that Drosophila Sds22 binds to all
four Drosophila PP1s and shares an overlapping phenotype with PP1 β9c. We also show that two previously
postulated PP1 targets, Spaghetti Squash and Moesin are hyper-phosphorylated in sds22 mutants. This
function is shared by the human homologue of Sds22, PPP1R7. In summary, Sds22 is a conserved PP1
phosphatase regulatory subunit that controls cell shape and polarity.
Development and Cancer
Madrid|4-6 February 2008
65
16. NOTCH1 directly regulates interleukin 7 receptor α-chain expression
and controls progenitor expansion during intrathymic development
Sara González-García1, Marina García-Peydró1, Esteban Ballestar2, Manel Esteller2, José Luis de la Pompa3,
Adolfo A. Ferrando4 and María L. Toribio1
NOTCH1 signalling is essential for T-cell specification of multipotent hematopoietic progenitors seeding the
thymus and for progression along the T-cell lineage. Development of T cells in both humans and mice is also
dependent on the interleukin 7 receptor α-chain (IL-7Rα), which is required in mice for B lymphopoiesis
as well. Here we show that activated NOTCH1 binds to a conserved CSL-binding site in the human Il7r
promoter and directly regulates IL-7Rα transcription. Defective NOTCH1 signalling impaired IL-7Rα
expression specifically in T-lineage cells and resulted in a compromised expansion of the T-cell progenitor pool
during intrathymic development, which was rescued by IL-7Rα overexpression. The pathological counterpart
of this finding is demonstrated by the regulation of IL-7Rα expression downstream of NOTCH1 in T-cell
lymphoblastic leukaemias. Overall, these data implicate Il7r as a direct transcriptional NOTCH1 target in
normal and leukemic T-lineage cells and suggest that NOTCH1 regulates early T cell development in part by
controlling the stage- and lineage-specific expression of IL-7Rα.
Centro Nacionalde
Biología Molecular
“Severo Ochoa”
- CBM/CSIC - UAM,
Madrid, Spain
2.
Centro Nacional
de Investigaciones
Oncológicas - CNIO,
Madrid, Spain
3.
Centro Nacional de
Biotecnología - CNB/
CSIC, Madrid, Spain
4.
Institute for Cancer
Genetics, Columbia
University, New York,
USA
1.
Poster Session
66
CNIO
CANCER
CONFERENCES
2008
17. Eiger/TNFα-mediated expansion of apoptosis in mutant
for Drosophila T-box gene optomotor-blind
Makoto Umemori and Takashi Adachi-Yamada
Graduate School
of Science, Kobe
University, Kobe,
Japan SORST,
Japan Science and
technology Agency,
Kobe University, Kobe,
Japan
Members of the three extracellular protein families Bone Morphogenetic Proteins (BMP), Wnt, and Hedgehog
(Hh), called morphogen, provide signaling as positional information to cells for appropriate differentiation.
They also regulate various cellular processes such as cell proliferation, cell motility, planar cell polarity
and apoptosis. Therefore, ectopic or reduced activity of these signals results in a combination of defects
in each cellular process. These changes should cause various pathological phenotypes, such as abnormal
morphogenesis and tumorigenesis, although they have not been examined in detail.
The mutant of Drosophila T-box gene optomotor-blind (omb), a transcriptional target of a long-range morphogen
Decapentaplegic (Dpp, the Drosophila homolog of BMP2/4), shows various abnormal phenotypes in the wing
imaginal disc such as ectopic folding, local overgrowth and severe apoptosis that are dependent on c-Jun
N-terminal kinase (JNK). We previously demonstrated that the omb mutation also induces hyperactivation
of Hh signaling that leads to the above morphological phenotypes. In addition, we here elucidated that the
omb mutation also causes a reduction in expression of Wingless (Wg), another long-range morphogen that is
a homolog of Wnt. Although the severe apoptosis phenotype in the omb mutant is due to hyperactivated Hh
signaling, appropriate compensation of intrinsic wg expression suppresses most of the apoptosis. Together
with these, we found that aberration in the triple morphogenetic signalings simultaneously occurs in the omb
mutant, and that alteration of their balance affects cell survival ability.
Moreover, this severe apoptosis spreads from the JNK-activated cells to the outer cell population. This
expanded apoptosis is distinct from the typical JNK-dependent apoptosis seen in cell competition and
previously documented nonautonomous apoptosis in its range of expansion. Our recent study revealed that
the Drosophila TNFα homolog Eiger (Egr) plays a role for the expansion of apoptosis. Although the intrinsic
functions of Egr still remain unknown, we suspect that the diffusion of Egr elicits the expansion of apoptosis
based on the analogy with the diffusible nature of TNFα. Indeed, it has been assumed that Egr can be cleaved
from the cell surface as seen in the case of TNFα (Kauppila et al. 2003). However, Egr unexpectedly did not
seem to show this diffusible property with the majority located on the cellular membrane. This indicates that
Egr makes apoptosis expand without its diffusion. Further genetic evidence also supports a novel mechanism
to explain this phenomenon. In this model, a positive feedback loop exists between JNK activation and Egr
expression, thereby repeating relays for mutual activation.
Poster Session
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Notes
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Development and Cancer
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invited speakers
portfolio
A compilation of short scientific biographies of organizers and speakers in accordance
with the order of the program
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Takashi Adachi-Yamada, PhD
Associate Professor,
Department of Biology,
Graduate School of Science,
Kobe University,
Kobe, Japan
Takashi Adachi-Yamada, PhD, Associate Professor at the Kobe University in Japan, is a developmental
biologist whose work is focused on the balance between cell proliferation, differentiation and apoptosis,
during development of the fruit fly Drosophila.
He had had a broad interest in entomology and obtained his PhD from Nagoya University in Japan by
analysis of the gene for silkmoth prothoracicotropic hormone which stimulates insect metamorphosis
through activating ecdysone synthesis.
After obtaining a PhD, he started research using Drosophila genetics to analyze the function of the MAP
kinase superfamily in response to various environmental stresses at the Aichi Cancer Center Research
Institute in Japan. He showed that the stress-activated protein kinases (p38 and JNK) play important roles
under abnormally high or low levels of TGF-β signaling.
When he was an Assistant Professor in Nagoya University, he had an opportunity to be a visiting scientist in
the lab of Michael B. O’Connor (University of Minnesota) and stayed there for 1.5 years. During this time,
he observed that JNK also plays a role for nonautonomously-induced apoptosis of abnormally differentiated
cells. Even when each cell type is normal, inappropriate attachment with different types of cells may be
one of the triggers for detecting abnormal cell populations.
In addition to his above foci in restoration of development, he is now also interested in the maintenance
of adult tissues, which should also be achieved by balance between cell proliferation, differentiation and
apoptosis.
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Nicholas E. Baker, PhD
Professor of Molecular Genetics
Albert Einstein College of Medicine
New York, USA
Nick Baker received his PhD degree in 1986 from the MRC Laboratory of Molecular Biology in
Cambridge, UK, where he studied under Peter Lawrence. His doctoral research reported the cloning and
initial characterization of wingless, a founder member of the Wnt family of proteins that communicate
extracellular information during development. After postdoctoral research in Gerald M. Rubin’s laboratory
at the University of California at Berkeley, in 1991 he joined the Department of Molecular Genetics at
Albert Einstein College of Medicine in New York, being appointed Full Professor in 2003. The focus of
Dr, Baker’s lab has been to understand how extracellular signals regulate cells during development, for
example in the Drosophila neural retina. Genetic mosaics and other conditional genetic approaches are
used to elucidate the roles of endogenous signals in vivo. He is particularly interested in the developmental
control of growth and cell proliferation. Recent work from his laboratory has explored the phenomenon
of ‘cell competition’. The results indicate that wild type epithelial cells can actively kill, eliminate and
replace cells of certain other genotypes, and his laboratory has identified several genes involved.
Dr. Baker is a recipient of the Irma T. Hirschl Scholar Award (2003).
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Gines Morata, PhD
Professor
Centro de Biología Molecular “Severo Ochoa”, CBM/CSIC - UAM
Madrid, Spain
Prof. Ginés Morata is an expert in Developmental Biology of Drosophila, specialty on which he has been
working for over 35 years. He obtained his PhD in the University of Madrid under the supervision of Dr.
A. Garcia-Bellido. During that period he developed (in collaboration with Dr. Pedro Ripoll) the Minute
technique and discovered the phenomenon of cell competition. After a postdoc period at the Laboratory
of Molecular Biology in Cambridge (UK), where he worked among other things on the role of engrailed
on comparmentalisation, he returned to Spain to work at the Centro de Biología Molecular in Madrid.
For a long time his principal scientific interest was the study of compartments in Drosophila and the
function of Hox genes and in particular those of the Bithorax Complex. Experiments carried out in his lab
demonstrated the genetic structure of the Bithorax Complex, constituted by the Ubx, abd-A and Abd-B
genes. These genes were later found to be present in the Hox complex of all animal species.
In more recent years he has been interested in the mechanisms regulating size and growth in the imaginal
discs and the events leading to misregulation of growth that often result in pathological situations such as
tumours. He is also studying the role of apoptosis and cell competition in the formation and progression
of tumours in the imaginal discs.
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Eduardo Moreno, PhD
Cellular Competition Junior Group Leader,
Molecular Oncology Programme,
Centro Nacional de Investigaciones Oncológicas - CNIO
Madrid, Spain
Eduardo Moreno was born in Madrid in 1970. He started his PhD working on the yellow method (Calleja,
M; Moreno, E, et al. Science, 1996), a mutagenesis scheme that led to the discovery of several new genes
of interest at the lab of Doctor Gines Morata in the Centro de Biología Molecular “Severo Ochoa” (CBM).
Among the genes identified with this method, Eduardo found the gene caudal and showed it was the gene
responsible for the formation of identity of the last segment in Drosophila, including the gene caudal among
the group of homeotic genes (Moreno, E. y Morata, G. Nature, 1999). For his PhD work, Eduardo Moreno
received the Extraordinary Award from the Universidad Autónoma de Madrid and the Young Scientists
Award Innogenetics from the Sociedad Española de Bioquímica y Biología Molecular (SEBBM).
Later, as a postdoctoral fellow, he started to study the phenomenon of “cell-competition”, a work started
at the laboratory of Doctor Gines Morata and continued at the laboratory of Profesor Konrad Basler in
Zurich. They obtained evidence that proliferating cells compete for the internalization of extracellular
factors promoting growth and survival. Cells that compete more favourable for those factors, proliferate and
survive, whereas cells that can not compete favourably die by apoptosis. (Moreno, E; Basler, K y Morata, G.
Nature, 2002). For this work Eduardo was awarded the prize for the best paper published at the CBM in
the year 2002 and the Young Investigator Award from the Brupbacher Foundation against cancer.
In the laboratory of Profesor Konrad Basler, Eduardo has continued studying the phenomenon of cellcompetition (Moreno, E. y Basler, K. Cell 2004).
Since october 2004 is a junior group leader at CNIO.
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David A. Shafritz, MD
Director, Marion Bessin Liver Research Center
Professor of Medicine, Cell Biology and Pathology
Albert Einstein College of Medicine
New York, USA
Dr. Shafritz is Professor of Medicine, Cell Biology and Pathology at the Albert Einstein College of Medicine
and Director of the Marion Bessin Liver Research Center. He received his MD. degree from the University
of Pennsylvania, Philadelphia, obtained postdoctoral research training at the National Institute of Health,
Bethesda, MD and advanced medical training in Gastroenterology and Hepatology at Massachusetts General
Hospital and Harvard Medical School, Boston, MA. Dr. Shafritz has extensive background in molecular
biology and for the past 35 years has been studying liver biology and pathobiology at the molecular level.
His recent research has been in liver cell growth control, liver regeneration and restoration of liver mass
and function through cell transplantation. Studies in his laboratory were the first to show that the normal
rat liver can be repopulated by early, pre-commitment fetal liver stem/progenitor cells. The level of liver
repopulation in the normal liver by these cells far exceeds that observed with any other cell type used to
date, including hematopoietic stem cells, cord blood stem cells, mesenchymal stem cells, embryonic stem
cells and hepatic-derived cell lines. Recently, his group has discovered that transplanted rat fetal liver
stem/progenitor cells replace host hepatocytes by cell competition, a mechanism described originally in
Drosophila during wing development and his current research is directed toward determining the molecular
mechanism(s) regulating cell competition in the mammalian liver. Dr. Shafritz and his colleagues have also
shown that fetal liver stem/progenitor cells can be transduced with lentiviruses and the transduced cells
maintain expression of a reporter gene for months after their expansion in vivo. His ultimate aspiration, as
a Physician/Scientist, is to develop the basic understanding and technology to bring cell transplantation to
clinical application in the treatment of inherited and acquired human liver diseases.
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Napoleone Ferrara, MD
Genentech, Inc,
South San Francisco, USA
Dr. Ferrara obtained his MD degree from the University of Catania Medical School in Italy in 1981. He
joined Genentech Inc. in 1988 after doing his postdoctoral research at the University of California at San
Francisco. At present, he is the Genentech Fellow in the Genentech Research Organization. Dr. Ferrara’s
main research interest are the biology of angiogenesis and the identification of its key regulators. His work
on VEGF-A resulted in the development of bevacizumab, the first anti-angiogenic agent to be approved
by the FDA for cancer therapy. Dr. Ferrara authored or co-authored over 250 scientific publications. He
is also the recipient of several awards, including the American-Italian Cancer Foundation Prize (2004),
the AACR Bruce F. Cain Memorial Award (2005), the Grand Prix Lefoulon-Delalande-Institut de France
(2005), the Passano Award (2006), the General Motors Cancer Research Award (2006), the C. Chester
Stock Award (2007), the ASCO Science of Oncology Award (2007) and a degree “honoris causa” from the
University of Eastern Piedmont, Italy (2007). In 2006 Dr. Ferrara was elected to the National Academy
of Sciences, USA.
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Luis F. Parada, PhD
Chairman/Professor
Department of Developmental Biology
University of Texas Southwestern Medical Center
Dallas, USA
Luis F. Parada grew up in Bogota, Colombia. He obtained a BS from the University of Wisconsin and a
PhD in Biology from MIT in 1985 identifying oncogenes in human cancer. He was a Damon Runyon and
later Helen Hay Whitney Postdoctoral Fellow at the Pasteur Institute. From 1988 to 1994, he headed
the Molecular Embryology Section at the NCI in Frederick, Maryland. His work there centered on the
identification and characterization of Trk receptor tyrosine kinases as physiological neurotrophin receptors.
In 1994 Dr. Parada moved to the University of Texas Southwestern Medical Center at Dallas as inaugurating
Director of the Center for Developmental Biology. During his time in Dallas, Dr. Parada has continued his
studies of nerve cell survival and regeneration and has renewed his attention on cancer with emphasis
on the nervous system. His laboratory uses mouse models to study Neurofibromatosis, cancers of the
nervous system, neural development and spinal cord injury. Dr. Parada is Chairman of the Department of
Developmental Biology and holds the Diana and Richard C. Strauss Distinguished Chair in Developmental
Biology, is Director of the Kent Waldrep Foundation Center for Basic Neuroscience Research, and is an
American Cancer Society Professor. He is a Fellow of the American Academy of Arts and Sciences and the
Institute of Medicine – National Academy of Sciences.
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Miguel Torres, PhD
Departamento de Biología del Desarrollo Cardiovascular
Centro Nacional de Investigaciones Cardiovasculares - CNIC
Instituto de Salud Carlos III
Madrid, Spain
Miguel Torres received his Master in Biology from the Complutense University of Madrid in 1986, and his
PhD in Biochemistry and Molecular Biology by the Autonomous University of Madrid in 1991. The subject
of his doctoral studies, carried out in Lucas Sánchez’s laboratory (CIB-CSIC), was the genetic study of early
Drosophila development. During his postdoc with Peter Gruss at the Max Planck Institute for Biophysical
Chemistry (Göttingen, Germany), his use of directed mutations in mice made an important contribution to
elucidating the multiple functions played by the pax gene family during embryonic development. Miguel
Torres was awarded the title of CSIC Research Scientist at the Spanish National Center for Biotechnology
(Centro Nacional de Biotecnología: CNB, Madrid) in 1996, where he built an internationally recognized
team specializing in the study of genetic mechanisms and cell signaling pathways implicated in vertebrate
embryonic development. In 2004 he was named Head of the Department of Immunology and Oncology at
the CNB, and in 2007 he moved his research group to the CNIC, where he took up the position of Head of
the Department of Cardiovascular Developmental Biology.
Selected References:
N. Mercader et al.,and M. Torres (1999). Conserved regulation of proximodistal limb axis development by
Meis1/Hth. Nature, 402, 425-429.
C. Clavería et al., and M. Torres (2002) GH3, a novel proapoptotic domain in Drosophila Grim, promotes
a mitochondrial death pathway. EMBO J. 21, 3327-3336
Nadia Mercader et al., and M. Torres (2005) Proximodistal identity during vertebrate limb regeneration is
regulated by Meis homeodomain proteins Development, 132:4131-42
Carlos G. Arques et al., and M. Torres (2007) Mouse limb mesenchyme is compartmentalized along the
dorso-ventral but not the proximo-distal or anterior-posterior axes Development, 134:3713-22
Marit J. Boot, C. Henrik Westerberg, Juanjo Sanz-Ezquerro, Ronen Schweitzer, M. Torres and James Sharpe
(2007) In vitro whole-organ imaging: Quantitative 4D analysis of growth and dynamic gene expression in
mouse limb buds. Nature Methods, in press
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Gijs R. van den Brink, PhD
Chief laboratory of Gastroenterology & Hepatology
Leiden University Medical Center
Leiden, The Netherlands
Gijs van den Brink received his medical degree at the Academic Medical Center of the University of
Amsterdam. He became involved in basic research during a year in a laboratory at Tufts University in Boston
while working on the regulation of intestine specific gene expression. As a PhD student in Amsterdam he
studied the role of morphogenetic signaling pathways in the gut and found a role for Hedgehog signaling
in the specification of cell fate in the adult gastrointestinal tract. After obtaining his PhD Gijs started his
training as a Gastroenterologist. He worked three years as a resident in Internal Medicine in Amsterdam,
two years in Gastroenterology at Geneva University in Switzerland and will finish his training at Leiden
University in the Netherlands, where he is now the chief of the laboratory of Gastroenterology. His research
focuses on the mechanisms that maintain morphostasis of the epithelium of the adult gut and the way
morphostasis is deregulated during inflammation and carcinogenesis. His research involves in vitro
experiments, animal models for inflammatory bowel disease and colorectal cancer and phase I and II
clinical trials.
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María A. Blasco, PhD
Basic Research Vicedirector
Molecular Oncology Programme Director
Telomeres and Telomerase Group Leader
Centro Nacional de Investigaciones Oncológicas - CNIO
Madrid, Spain
In 1993, María A. Blasco obtained her PhD in Biochemistry and Molecular Biology at the Universidad
Autónoma de Madrid after her work at Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM, Madrid)
under the supervision of Dr. Margarita Salas.
That same year, Blasco joined the Cold Spring Harbor Laboratory (Cold Spring Harbor-USA) as Postdoctoral
Fellow under the leadership of Carol.W. Greider. As Postdoctoral Fellow, María A. Blasco cloned one of the
mammalian telomerase genes and generated the first telomerase knockout mouse. It was during this time
that she was also appointed a Fellow of the Leukaemia Society of America. In 1997, María returned to
Madrid as Staff Investigator at Centro Nacional de Biotecnología (CSIC), where she continued her work on
the development of mouse models for the study of telomerase in cancer and ageing.
Together with her research group she moved to the CNIO in 2003 as Director of the Molecular Oncology
Programme and Leader of the Telomeres and Telomerase Group.
Since her return to Spain, Blasco has been the recipient of several honours, such as the FEBS Award,
the Swiss Bridge Award to Research in Cancer, and the National Oncology Award. Most recent recognition
for her outstanding work in the field has included the Josef Steiner Cancer Research Award (2003), the
“Carmen y Severo Ochoa” Award for research in Molecular Biology (2005), the “Rey Jaime I” Award for
Biomedical Research” and the EMBO Gold Medal (2004). She also serves on the Highlight Advisory Panel
of Nature Reviews Cancer. She is an elected EMBO Member since the year 2000, a Young Global Leader
by the World Economic Forum since 2006, and a Member the Academia Europaea since 2006. María A.
Blasco is also a member of Faculty 1000 (“stem cells and regeneration”). María A. Blasco, with more than
100 original papers, has made significant contributions to the field of telomeres and telomerases and the
role they play in ageing and cancer.
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Ruth Lehmann, PhD
HHMI Investigator
Director, Skirball Institute
Professor of Cell Biology
NYU School of Medicine
New York, USA
Born in Cologne, Germany, Ruth Lehmann was introduced to developmental biology first in Gerold
Schubiger’s lab at the University of Washington, Seattle and then during her Diploma thesis in the
laboratory of the late Jose Campos Ortega at the University of Freiburg, Germany, where she described the
neurogenic genes in Drosophila. She completed her doctoral thesis in 1985 in the laboratory of Christiane
Nuesslein-Volhard, where she participated in the identification of maternal effect genes that organize the
embryonic axis in Drosophila. After postdoctoral training in Tübingen and at the Medical Research Council
in Cambridge, UK in the laboratory of the late Mike Wilcox, she joined the Whitehead Institute and the
faculty of MIT in 1988. Molecular characterization of nanos, pumilio and oskar in her lab showed that RNA
localization within a cell is tightly linked to translational regulation.
In 1996, Dr. Lehmann moved to the Skirball Institute at NYU School of Medicine where she is an
investigator of the Howard Hughes Medical Institute. Here she used genetics and live-imaging methods to
demonstrate the role of lipid signaling in germ cell migration. Her lab uses genetic, molecular and high
resolution imaging approaches to study germ cell specification, migration and survival in the embryo and
germ line stem cell maintenance in the adult.
Dr. Lehmann is director of the Helen and Martin Kimmel Stem Cell Center at NYU. In November 2006
she was appointed Director of the Skirball Institute and named Laura and Isaac Perlmutter Chair of
Developmental Genetics. She is a member of the American Academy of Arts Sciences and the foreign
associate of the National Academy of Sciences.
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Haifan Lin, PhD
Professor and Director of the Yale University Stem Cell Center
New Haven, USA
Dr. Lin’s work is focused on the self-renewing mechanism of Drosophila and mouse germline stem cells
as well as human embryonic stem cells. In addition, Dr. Lin studies germline development and cancers
related to the malignant proliferation of stem cells. Dr. Lin received his BS degree from Fudan University,
and his PhD degree from Cornell University. Following his postdoctoral research at the Carnegie Institution
of Washington, he joined the faculty of Duke University Medical School in 1994, where he rose to the rank
of Full Professor. He co-founded and co-directed the Duke Stem Cell Research Program. Dr. Lin moved
to Yale in 2006 to establish the Yale Stem Cell Center. Dr. Lin received numerous awards and honors,
including the American Cancer Society Junior Faculty Research Award (1996), the March of Dimes Basil
O’Connor Scholar Research Award (1996), the David and Lucile Packard Fellowship for Science and
Engineering (1996), Member of the Connecticut Academy of Science and Engineering (2007-), and the
G. Harold and Leila Y. Mathers Award (2007). He has served on the NIH study sections (1998-2005), the
International Society for Stem Cell Research (2002-), the Editorial Boards of Cell Stem Cells (2007-) and
Stem Cells (2005-), and has been invited as a Featured Editor for Nature Reports Stem Cells. He has also
served on the Scientific Advisory Boards of several leading research institutions and biotech companies,
among other extramural activities.
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Isidro Sánchez-García, MD, PhD
Senior Staff Researcher CSIC
Experimental Therapeutics and Translational Oncology Program,
Instituto de Biologia Molecular y Celular del Cancer - IBMCC
CSIC/Universidad de Salamanca,
Salamanca, Spain
Isidro Sánchez-García is a Senior Staff Scientist at the Instituto de Biologia Molecular y Celular del
Cancer (IBMCC) of Spanish Research Council (CSIC). He learnt and practiced Medicine before completing
his PhD at University of Salamanca. Isidro was a postdoctoral fellow at the Medical Research Council’s
Laboratory of Molecular Biology in Cambridge before appointment to his current position in 1997.
Isidro’s research interest is in the study of cancer development and its relationship with stem cells with
a view to improving our understanding of the pathogenesis and treatment of cancer. His research group
hopes this investigation will result not only in new concepts in cancer biology and development, but also
it will provide the basis for the development of both a new strategy in cancer therapy and new methods for
assessing treatment efficacy.
Isidro is a Fellow of the José Carreras International Leukemia Foundation and co-founder of Oncostem
Pharma.
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Allan C. Spradling, PhD
Director
Department of Embryology/HHMI
Carnegie Institution
Baltimore, USA
Allan C. Spradling, PhD directs the Department of Embryology of the Carnegie Institution in Baltimore, and
is also a Howard Hughes Medical Institute Investigator, and Adjunct Professor of Biology at Johns Hopkins
University. Spradling has contributed in several ways to developing technology that allows Drosophila
tissues to be genetically manipulated with unsurpassed precision. In 1982 he and Gerry Rubin developed Pelement mediated transformation, and a few years later Spradling’s group began to generate mutant strains
using single transposon insertion. Expanded as part of the Berkeley Drosophila genome project, again in
collaboration with Rubin, large libraries of single-insert strains now provide the research community with a
functional handle on more than 60% of Drosophila genes. Spradling’s studies of the Drosophila ovary have
addressed a wide variety of topics, including gene amplification, chromatin, germline cyst formation, cell
migration, mitochondrial inheritance, hormonal regulation, and have renewed interest in long neglected
organelles such as the fusome, nuage and the Balbiani body. During the last 12 years, the Spradling lab
has applied genetic tools for lineage labeling to demonstrate that Drosophila adults contain many kinds of
stem cells, both in the ovary and in other tissues such as the midgut. Deciphering how these stem cells are
controlled within their normal tissue microenvironments allowed stem cell niches to be characterized in
detail for the first time. Spradling is a former President of the Society for Developmental Biology and of the
Genetics Society of America. He has been a member of the National Academy of Sciences since 1988.
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Konrad Basler, PhD
Professor,
Institute of Molecular Biology
University of Zurich
Zurich, Switzerland
1980 - 1986
1986 - 1989
1990 - 1993
1993 - 1996
1997 - 1999
1999 -
Studies of Biology and Biochemistry at the University of Zurich
Diploma work at the Institute of Molecular Biology I supervisor: Prof. Charles Weissmann
Ph. D. Thesis with Prof. Ernst Hafen at the Zoology Institute, University of Zurich
Postdoctoral work with Drs. Tom Jessell and Gary Struhl at Columbia University, New York
Assistant Professor, Zoology Institute, University of Zurich
Professor, Zoology Institute, University of Zurich
Professor, Institute of Molecular Biology, University of Zurich
University Examinations
1986
Diploma in Biochemistry
1989
Ph.D. in Developmental Biology
Honors and Awards
1986
Diploma work “mit Auszeichnung”
1989
Ph.D. Thesis “mit Auszeichnung”
1991
European Drosophila Research Junior Award
1996
Friedrich Miescher Award
1996
FEBS Anniversary Prize
1997
National Latsis Prize
1999
EMBO Gold Medal
2000
Louis-Jeantet Prize for Medicine
2005
Election into Research Council of the Swiss National Science Foundation
2007
Directorship Institute of Molecular Biology
Publications 2007
T. Aegerter-Wilmsen, C. M. Aegerter, E. Hafen and K. Basler (2007). Model for the regulation of size in the
wing imaginal disc of Drosophila. Mech Dev. 124, 318-326.
G. Hausmann, C. Bänziger and K. Basler (2007). Helping Wingless take flight: how WNT proteins are
secreted. Nature Rev Mol Cell Biol. 8, 331-336.
J. Bischof, R. K. Maeda, M. Hediger, F. Karch and K. Basler (2007). An optimized transgenesis system for
Drosophila using germ-line-specific φC31 integrases. Proc Natl Acad Sci USA 104, 3312-3317.
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Duojia Pan, PhD
Department of Molecular Biology and Genetics,
Johns Hopkins University School of Medicine,
Baltimore, USA
I received my B.S. degree in Biochemistry from Beijing University in China (1988). I obtained my PhD
degree in Biological Chemistry from UCLA (1993), where I studied transcriptional regulation in early
Drosophila embryos with Albert Courey. From 1993 to 1998, I was a Jane Coffin Child Postdoctoral
Fellow in the laboratory of Gerald Rubin where I studied hedgehog and Notch signaling. In 1998, I
joined the Department of Physiology at University of Texas Southwestern Medical Center (Dallas, Texas)
as an Endowed Scholar in Biomedical Research and was promoted to Associate Professor with tenure in
2004. In December 2004, I joined the Department of Molecular Biology and Genetics at Johns Hopkins
University School of Medicine.
My laboratory uses Drosophila as a genetic model to investigate the molecular mechanisms that control the
growth of developing tissues. We are also interested in applying the insights we have learned in Drosophila
to understanding growth control in Mammals. Our earlier work provided key insights into the molecular
function of the Tuberous Sclerosis Complex tumor suppressor proteins (TSC1 and TSC2). Our current work
focuses on the Hippo signaling pathway in organ size control and tumorigenesis.
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Juergen A. Knoblich, PhD
Deputy Scientific Director
Institute of Molecular Biotechnology of the Austrian Academy of Sciences - IMBA
Vienna, Austria
Jürgen Knoblich started his scientific carreer as a graduate student at the Max Planck Institute in Tübingen.
His PhD thesis was on Genetic Analysis of Cyclin Proteins during Drosophila Embryonic Development and
was supervised by Dr. Christian Lehner. After his PhD, Jürgen Knoblich joined the laboratory of Drs. Yuh
Nung and Lily Jan at the University of California, San Francisco as post doctoral fellow. During this time,
he started to work on asymmetric cell division, a topic that has remained the main focus of his research
ever since.
In 1997, Jürgen Knoblich returned to Europe to become a group leader at the Institute of Molecular
Pathology (I.M.P.) in Vienna, Austria. In 2004, he moved next door to the newly founded Institute of
Molecular Biotechnology of the Austrian Academy of Sciences (IMBA). He became a senior scientist and
was appointed deputy scientific director of the institute in 2005.
Jürgen Knoblich has received several awards such as the Anniversary Award of the Federation of the
European Biochemical Societies (FEBS) in 2001, the Young Investigator Award of the European Molecular
Biology Organisation (EMBO) in 2001 and the Early Career Award of the European Life Scientist
Organization (ELSO) in 2003.
Jürgen Knoblich is a member of the International Society for Stem Cell Research (ISSCR) since 2002 and
has been elected member of the European Molecular Biology Organisation (EMBO) in 2002. Since 2005,
he serves on the EMBO fellowship committee. Jürgen Knoblich is also member of the editorial board of
Current Biology since 2002 and the European Journal of Cell Biology since 2004.
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Iswar K. Hariharan, PhD
Professor of Cell and Developmental Biology
Department of Molecular and Cell Biology
University of California,
Berkeley, USA
Iswar Hariharan is a Professor in the Department of Molecular and Cell Biology at the University of
California, Berkeley.
Iswar Hariharan was born in India and moved to Australia when he was 12 years old. He obtained his
medical degree at the University of Sydney in 1984. After completing a one-year hospital residency,
he worked as a graduate student in the laboratory of Jerry Adams and Suzanne Cory at The Walter and
Eliza Hall Institute of Medical Research, Melbourne where he studied the molecular basis of chronic
myelogenous leukemia. He received his PhD degree in 1989. He was a postdoctoral fellow with Gerald
Rubin at the University of California, Berkeley from 1989 to 1992 where he began to work with Drosophila.
He joined the Massachusetts General Hospital Cancer Center and Harvard Medical School as an Assistant
Professor in 1992 and was promoted to Professor in 2003. In 2004, he moved to the University of
California, Berkeley where he is a Professor of Cell and Developmental Biology.
His laboratory uses a genetic approach to study the mechanisms that regulate growth during normal
development as well as the regulation of tissue regeneration.
For a more detailed description of the research visit the following websites:
Hariharan Lab website: http://mcb.berkeley.edu/labs/hariharan/
MCB Faculty Page: http://mcb.berkeley.edu/faculty/CDB/hariharani.html
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Georg Halder, PhD
MD Anderson Cancer Center
The University of Texas
Houston, USA
Georg Halder obtained his PhD in 1996 from the University of Basel, Switzerland, where he worked in
Walter Gehring’s group. His PhD dissertation was on the function of the Drosophila Pax6 gene eyeless
during eye development. His most significant contribution was the finding that overexpression of Eyeless
was sufficient to induce the development of extra eyes on adult structures such as legs and wings. Dr.
Halder then worked as a postdoctoral fellow in Sean Carroll’s laboratory in Madison, Wisconsin, from 19962000, where he worked on Drosophila and butterfly wing development and evolution. His focus was on
the function and evolution of the homeotic gene Ultrabithorax and the selector gene complex Vestigial and
Scalloped. In 2000, he moved to the MD Anderson Cancer Center in Houston, Texas, where his research
interests focus on growth control in Drosophila imaginal discs. Particularly, his laboratory has contributed
to the discovery of the Hippo signaling pathway, a key regulator of organ growth. This work has led to a
deeper understanding of the mechanisms that control cell proliferation and growth during development.
Development and Cancer
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89
Maria Dominguez, PhD
Full Professor
Universidad Miguel Hernandez – CSIC
Alicante, Spain
Following her PhD at Universidad Autonoma de Madrid (UAM) Spain in 1993, Dr. Dominguez undertook
postdoctoral research at the University of Zurich, where her research focused on cell signalling and pattern
formation in the retina of Drosophila. In 1997, she moved to UK and joined the Peter A. Lawrence’s
group at the MRC Laboratory of Molecular Biology in Cambridge, where she worked on mechanisms of
growth control and pattern formation using Drosophila eye as a model. During these years, Dr. Dominguez
published seminal papers on the role of Hedgehog, EGFR and Notch in growth control and pattern
formation in the Drosophila eye. In 2000, she obtained a Tenured Research position from the Spanish
Research Council (CSIC) at the Instituto de Neurociencias de Alicante (Spain). From 2002 to 2005, Dr.
Dominguez was Deputy Director of the Instituto de Neurociencias, and she has recently been promoted
to Full Professor. In 2000, Dr. Dominguez was selected EMBO Young Investigator and since 2007 Dr.
Dominguez is a member of EMBO. Her research group focus on the mechanisms of cancer and growth
control by the Notch signalling pathway, using Drosophila and C. elegans as models. She has been invited
speaker at numerous national and international meetings and serves as a member of the editorial board of
the journal ‘Developmental Dynamics’ since 2005. Recent works have revealed unsuspected connections
between the Notch pathway and the epigenetic silencing pathways and the survival pathways PI3K/AKT/
PTEN in growth control and tumorigenesis.
Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins
SL, Bhagat G, Agarwal AM, Basso G, Castillo M, Nagase S, Cordon-Cardo C, Parsons R, Zúñiga-Pflücker
JC, Dominguez M, Ferrando AA. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell
leukemia. Nat Med. 2007 Oct;13(10):1203-10. Epub 2007 Sep 16.
Dominguez M.Interplay between Notch signaling and epigenetic silencers in cancer. Cancer Res. 2006
Sep 15;66(18):8931-4. Review.
Ferres-Marco D, Gutierrez-Garcia I, Vallejo DM, Bolivar J, Gutierrez-Aviño FJ, Dominguez M. Epigenetic
silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature. 2006 Jan
26;439(7075):430-6.
Dominguez M, Ferres-Marco D, Gutierrez-Aviño FJ, Speicher SA, Beneyto M. Growth and specification of
the eye are controlled independently by Eyegone and Eyeless in Drosophila melanogaster. Nat Genet. 2004
Jan;36(1):31-9. Epub 2003 Dec 14.
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Development and Cancer
Madrid|4-6 February 2008
List of Invited Speakers
and Participants
Calendar of CNIO Activities 2008
Previous CNIO Cancer Conferences
92
CNIO
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CONFERENCES
2008
Takashi Adachi-Yamada
yamadach@kobe-u.ac.jp
Graduate School of Science, Kobe University, Kobe, Japan
Nicholas E. Baker
nbaker@aecom.yu.edu
Albert Einstein College of Medicine, New York, USA
Konrad Basler
Konrad.Basler@molbio.uzh.ch
University of Zurich, Zurich, Switzerland
María A. Blasco
mblasco@cnio.es
Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
Gijs R. van den Brink
g.r.van_den_brink@lumc.nl
Leiden University Medical Center, Leiden, The Netherlands
Maria Dominguez
m.dominguez@umh.es
Universidad Miguel Hernandez - CSIC, Alicante, Spain
Napoleone Ferrara
nf@gene.com
Genentech Inc., San Francisco, USA
Georg Halder
ghalder@mdanderson.org
The University of Texas, M.D. Anderson Cancer Center, Houston, USA
Iswar Hariharan
ikh@berkeley.edu
University of California, Berkeley, USA
Jürgen Knoblich
juergen.knoblich@imba.oeaw.ac.at
Institute of Molecular Biotechnology of the Austrian Academy of Sciences - IMBA, Vienna, Austria
Invited Speakers and Organizers
Development and Cancer
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93
Ruth Lehmann
lehmann@saturn.med.nyu.edu
Howard Hughes Medical Institute and the Kimmel Center for Biology and Medicine of the Skirball Institute, New York, USA
Haifan Lin
haifan.lin@yale.edu
Yale University, New Haven, USA
Gines Morata
gmorata@cbm.uam.es
Centro de Biología Molecular “Severo Ochoa” - CBM/CSIC - UAM, Madrid, Spain
Eduardo Moreno
emoreno@cnio.es
Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
Duojia Pan
djpan@jhmi.edu
Johns Hopkins University School of Medicine, Baltimore, USA
Luis Parada
luis.parada@utsouthwestern.edu
UT Southwestern Medical Center, Dallas, USA
Isidro Sánchez-García
isg@usal.es
Instituto de Biologia Molecular y Celular del Cancer - IBMCC/CSIC Universidad de Salamanca, Salamanca, Spain
David A. Shafritz
shafritz@aecom.yu.edu
Albert Einstein College of Medicine, New York, USA
Allan Spradling
spradling@ciwemb.edu
Carnegie Institution, Baltimore, USA
Miguel Torres
mtorres@cnic.es
Centro Nacional de Investigaciones Cardiovasculares - CNIC, Madrid, Spain
Invited Speakers and Organizers
94
CNIO
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2008
Raquel Almeida
ralmeida@ipatimup.pt
Institute of Molecular Pathology and Immunology of the University of Porto - IPATIMUP, Porto, Portugal
Latifa Bakiri
lbakiri@cnio.es
Research Institute of Molecular Pathology - IMP, Vienna, Austria
Present address: Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
Francesco Blasi
francesco.blasi@ifom-ieo-campus.it
FIRC Institute of Molecular Oncology, Milan, Italy
Fernando Casares
fcasfer@upo.es
Centro Andaluz de Biología del Desarrollo - CABD/CSIC - UPO, Sevilla, Spain
Cristina Clavería Izquierdo
cclaveria@cnic.es
Centro Nacional de Investigaciones Cardiovasculares - CNIC, Madrid, Spain
Paola Gallinari
paola_gallinari@merck.com
Istituto di Ricerca di Biologia Molecolare - IRBM, Rome, Italy
Beatriz Garcia Fernandez
beatrizf@igc.gulbenkian.pt
Instituto Gulbenkian de Ciencia, Lisbon, Portugal
Offer Gerlitz
offerg@ekmd.huji.ac.il
The Hebrew University, Jerusalem, Israel
Almudena González Gomez Navarro
pjaen@isciii.es
Instituto de Salud Carlos III - ISCIII, Madrid, Spain
Acaimo Gonzalez-Reyes
agonrey@upo.es
Centro Andaluz de Biología del Desarrollo - CABD/CSIC - UPO, Sevilla, Spain
Participants
Development and Cancer
Madrid|4-6 February 2008
95
Heidrun Herbrüggen
heidi.herbrueggen@gmx.at
Medical University of Vienna, Vienna, Austria
Héctor Herranz
hector.herranz@irbbarcelona.org
Institute for Research in Biomedicine - IRB, Barcelona, Spain
Tatsushi Igaki
igaki@med.kobe-u.ac.jp
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, USA
Florence Janody
fjanody@igc.gulbenkian.pt
Instituto Gulbenkian de Ciência, Oeiras, Portugal
Miguel Manzanares
mmanzanares@cnic.es
Centro Nacional de Investigaciones Cardiovasculares - CNIC, Madrid, Spain
Maria del Carmen Marin Vieira
carmen.marin@unileon.es
Universidad de Leon/Instituto Biomedicina, Leon, Spain
Francisco A. Martin
famartin@cbm.uam.es
Centro de Biología Molecular “Severo Ochoa” - CBM/CSIC - UAM, Madrid, Spain
Maria Dolores Martin Bermudo
mdmarber@upo.es
Centro Andaluz de Biología del Desarrollo - CABD/CSIC - UPO, Sevilla, Spain
Marco Milan
marco.milan@irbbarcelona.org
Institute for Research in Biomedicine - IRB, Barcelona, Spain
Javier Morante
jm184@nyu.edu
New York University, New York, USA
Participants
96
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2008
Michael Oertel
moertel@aecom.yu.edu
Albert Einstein College of Medicine, New York, USA
Hyangyee Oh
hoh@waksman.rutgers.edu
Waksman Institute, Rutgers University, Piscataway, USA
Amir Orian
mdoryan@tx.technion.ac.il
Rappaoprt Research Center, Technion-Israel Institute of Technology - IIT, Haifa, Israel
Yongkyu Park
parky1@umdnj.edu
University of Medicine and Dentistry of New Jersey - UMDNJ, New Jersey Medical School, Newark, USA
Jose C. Pastor-Pareja
jcp45@email.med.yale.edu
Yale University School of Medicine, New Haven, USA
Francisco X. Real Arribas
preal@cnio.es
Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
Christa Rhiner
crhiner@cnio.es
Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
Isabel Rodriguez
irodriguez@cbm.uam.es
Centro de Biología Molecular “Severo Ochoa” - CBM/CSIC - UAM, Madrid, Spain
Miguel Angel Rodriguez Marcos
marmarcos@cbm.uam.es
Centro de Biología Molecular “Severo Ochoa” - CBM/CSIC - UAM, Madrid, Spain
Ernesto Sanchez-Herrero
esherrero@cbm.uam.es
Centro de Biología Molecular “Severo Ochoa” - CBM/CSIC - UAM, Madrid, Spain
Participants
Development and Cancer
Madrid|4-6 February 2008
97
Evgeny Shlevkov
eshlevkov@cbm.uam.es
Centro de Biología Molecular “Severo Ochoa” - CBM/CSIC - UAM, Madrid, Spain
Nicolas Tapon
nicolas.tapon@cancer.org.uk
Cancer Research UK London Research Institute, London, UK
Aurélie Telliez
aurelie.telliez@fr.netgrs.com
Institut de Recherches Servier, Croissy Sur Seine, France
Barry Thompson
Barry.Thompson@cancer.org.uk
Cancer Research UK London Research Institute, London, UK
Stefan Thor
steth@ifm.liu.se
Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden
Maria L. Toribio
mtoribio@cbm.uam.es
Centro de Biología Molecular “Severo Ochoa” - CBM/CSIC - UAM, Madrid, Spain
Makoto Umemori
058s352s@stu.kobe-u.ac.jp
Graduate School of Science, Kobe University, Kobe, Japan
Erwin Wagner
ewagner@cnio.es
Research Institute of Molecular Pathology - IMP, Vienna, Austria
Present address: Centro Nacional de Investigaciones Oncológicas - CNIO, Madrid, Spain
Participants
98
CNIO
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CONFERENCES
2008
>> February 2008
Development and Cancer – CNIO Cancer Conference
04/02/2008 - 06/02/2008
Organizers: Konrad Basler, Ginés Morata, Eduardo Moreno and Miguel Torres
Registration: www.cnio.es/ccc
Trasladando la Proteómica al laboratorio Clínico
12/02/2008
Organizers: Sociedad Española de Bioquímica Clínica y Patología Molecular, Grupo de Marcadores Tumorales
Registration: http://www.seqc.es
II Jornada Traslacional en Oncología Pediátrica: del Diagnóstico Molecular a la Clínica
22/02/2008
Organizers: Juan Cruz Cigudosa, Anna González-Neira, Javier Benítez, Instituto Roche
Registration: http://www.institutoroche.es
>> March 2008
CNIO-ONCOTRAIN Meeting: ” New battlefields in human cancer- Attacking in many fronts”
10/03/2008 - 11/03/2008
Organizers: ONCOTRAIN Program
Registration: www.cnio.es/meetings
>> April 2008
Jornada Científica COLOMICS: “Avances en cáncer de colón”
14/04/2008
Organizers: Felix Bonilla, Ignacio Casal, Antonio Garcia de Herreros y Alberto Muñoz
Registration: www.cnio.es/meetings
CASP Meeting
21/04/2008 - 22/04/2008
Organizers: Alfonso Krzysztof Fidelis, Andriy Kryshtafovych, John Moult, Burkhard Rost, Anna Tramontano, Michael Tress
and Alfonso Valencia
Registration: www.cnio.es/meetings
Calendar of CNIO Activities 2008
Development and Cancer
Madrid|4-6 February 2008
99
ENFIN – DREAM Conference: Assessment of Computational Methods in Systems Biology
28/04/2008 - 29/04/2008
Organizers: Alfonso Valencia, Pascal Kahlem; Co-Organizer: Ana Rojas Mendoza
Registration: www.cnio.es/meetings
>> May 2008
Marie Curie Gard: Interplay among Genetics, Epigenetics and non-coding RNAs
04/05/2008 - 07/05/2008
Organizers: Manel Esteller and George Calin
Registration: http://www.mc-gard.eu
>> June 2008
3rd ESO-CNIO Familial Cancer Conference
05/06/2008 - 06/06/2008
Organizers: Javier Benitez, Ros Eeles and Hans Vasen
Registration: www.cnio.es/meetings
Structure and Mechanisms of Essential Complexes for Cell Survival - CNIO Cancer Conference
23/06/2008 - 25/06/2008
Organizers: Niko Grigorieff, Eva Nogales and Jose María Valpuesta
Registration: www.cnio.es/ccc
EPIGENOME Meeting
26/06/2008 – 29/06/2008
Organizers: Oskar Fernandez-Capetillo, Ana Losada, María A. Blasco and the Epigenome network
>> November 2008
Signalling Upstream of mTOR - CNIO Cancer Conference
03/11/2008 - 05/11/2008
Organizers: Dario R. Alessi, Tomi P. Mäkelä and Montserrat Sanchez-Cespedes
Registration: www.cnio.es/ccc
Calendar of CNIO Activities 2008
100
CNIO
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2008
>> 2007
Molecular mechanisms in Lymphoid Neoplasm - CNIO Cancer Conference
Organizers: Elias Campo, Riccardo Dalla-Favera, Elaine S. Jaffe, Miguel Angel Piris
19/02/2007 - 21/02/2007
Myc and the Transcriptional Control of Proliferation and Oncogenesis - CNIO Cancer Conference
Organizers: Robert N. Eisenman, Martin Eilers, Javier León
11/06/2007 - 13/06/2007
Links Between Cancer, Replication Stress and Genomic Integrity- CNIO Cancer Conference
Organizers: Oscar Fernández-Capetillo, Jiri Lukas, Juan Méndez, André Nussenzweig
05/11/2007 - 07/11/2007
>> 2006
Telomeres and Telomerase - CNIO / Joséf Steiner Cancer Conference
Organizers: María A. Blasco, Jerry Shay
13/11/2006 - 15/11/2006
Medicinal Chemistry in Oncology
Organizers: Fernando Albericio, James R. Bischoff, Carlos García-Echeverria , Andrew Mortlock
02/10/2006 - 04/10/2006
Inflammation and Cancer
Organizers: Curtis Harris, Raymond DuBois, Jorge Moscat, Manuel Serrano
22/05/2006 - 24/05/2006
PTEN and the AKT route
Organizers: Ana Carrera, Pier Paolo Pandolfi, Peter Vogt
08/05/2006 - 10/05/2006
>> 2005
Cancer and Aging
Organizers: María A. Blasco, Kathy Collins, Jan Hoeijmakers, Manuel Serrano
07/11/2005 - 09/11/2005
MAP Kinases and Cancer
Organizers: Philip Cohen, Dundee, Roger Davis, Worcester, Chris Marshall, Ángel Nebreda
30/05/2005 - 01/06/2005
Previous CNIO Cancer Conferences
Development and Cancer
Madrid|4-6 February 2008
101
Animal Tumour Models and Functional Genomics
Organizers: Allan Balmain, Mariano Barbacid, Anton Berns, Tyler Jacks
07/03/2005 - 09/03/2005
>> 2004
Cadherins, Catenins and Cancer
Organizers: Amparo Cano, Hans Clevers, José Palacios, Franz Van Roy
29/11/2004 - 01/12/2004
Structural Biology of Cancer Targets
Organizers: Ernest Laue, Guillermo Montoya, Alfred Wittinhofer
27/09/2004 - 29/09/2004
>> 2003
Apoptosis and Cancer
Organizers: Gabriel Nuñez, Marisol Soengas, Scott Lowe
01/12/2003 - 03/12/2003
Small GTPases in Human Carcinogenesis
Organizers: Juan Carlos Lacal, Channing Der, Shuh Narumiya
16/06/2003 - 18/06/2003
Targeted Search for Anticancer Drugs
Organizers: Amancio Carnero, David H. Beach
17/03/2003 - 19/03/2003
>> 2002
Mechanisms of Invasion and Metastasis
Organizers: Joan Massagué, Richard Hynes
18/11/2002 - 20/11/2002
The Cell Cycle and Cancer
Organizers: Marcos Malumbres, Charles Sherr, Jiri Bartek
30/09/2002 - 02/10/2002
Cancer Epigenetics: DNA Methylation and Chromatin
Organizers: Manel Esteller, Stephen B. Baylin
29/05/2002 - 31/05/2002
Previous CNIO Cancer Conferences
CNIO Centro Nacional de Investigaciones Oncológicas
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Coordination and edition Sara Bertrand
Direction of art and producction Bocetocolor SL
Photographic archive CNIO
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