STEM CELLS AND CANCER GROUP

VICE-DIRECTION OF TRANSLATIONAL RESEARCH
MOLECULAR PATHOLOGY PROGRAMME | SteM ceLLS AnD cAnceR GRoUp
STEM CELLS AND
CANCER GROUP
Christopher Heeschen
Group Leader
Staff Scientists
Alexandra Aicher (since February),
Susana García, Bruno Sainz, Patricia
Sancho
Post-Doctoral Fellows
Maria Azevedo (until September),
Anamaria Balic (until July), Jorge
Dorado (until June), Sara Trabulo,
Yolanda Sánchez (until September)
Graduate Students
Álvaro Castells (since November),
Michele Cioffi, Anja Fries (since
September), Irene Miranda, Marina Roy
(since August), Alejandra Tavera (since
October), Sladjana Zagorac
Technicians
Sonia Alcalá, Emma Burgos, Magdalena
Choda (since September), Catarina L.
Reis, Marianthi Tatari (since May), Mireia
Vallespinos (since May)
Visiting Scientists
Patrick C. Hermann (until October),
Morten Draeby Sorensen
Christopher Heeschen DEU
Alexandra Aicher DEU
Susana García ESP
Patricia Sancho ESP
Sara Trabulo PRT
Álvaro Castells ESP
Michele Cioffi ITA
Anja Fries USA
Irene Miranda ESP
Marina Roy ESP
Alejandra Tavera MEX
Sladjana Zagorac SRB
Sonia Alcalá ESP
Emma Burgos ESP
Magdalena Choda POL
Catarina L. Reis PRT
Marianthi Tatari GRC
Mireia Vallespinos ESP
Morten Draeby Sorensen DNK
OVERVIEW
With the availability of more sophisticated model systems
and technologies it has now become evident that cancer
heterogeneity is even greater than anticipated from the
multiple genetic alterations, but it is also driven by the
phenotypic and functional heterogeneity and plasticity
within each subclone of the tumour. Indeed, pancreatic
cancer stem cells (CSCs) represent a subset of cancer cells,
for which we, and others, have provided conclusive evidence
that these cells represent the root of the disease by giving
rise to all the differentiated progenies within each cancer
subclone (FIGURE 1).
Scientific RepoRt 2013
“ Our
research should ultimately
allow us to develop novel multimodal
therapies to eliminate both CSCs,
as the root of pancreatic cancer,
and their differentiated progenies.
Targeted delivery of new therapies in
combination with advanced imaging
technologies will be achieved by
nanoparticle technology and tested
in well-designed clinical trials.”
Even more important, from a clinical perspective, these cells
are driving the metastatic behaviour of pancreatic cancer
and are the putative source for disease relapse. Therefore,
CSCs are responsible for the intraclonal heterogeneity of the
tumour and represent a crucial component for the development
of novel treatments. Noteworthy is the fact that CSCs do
not represent bona fide stem cells based on most stringent
criteria, nor do they necessarily arise from tissue stem cells.
Instead, CSCs have acquired certain features of stem cells.
While CSCs and their differentiated progenies demonstrate
an identical genetic ground state with respect to genetic
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SpAniSH nAtionAL cAnceR ReSeARcH centRe, cnio
alterations, as demonstrated by single-cell implantation
experiments, CSCs exhibit distinct gene expression profiles
that share modules with pluripotent stem cells. Most of the
genes involved in generating induced pluripotent stem cells
(iPS cells) − such as Nanog, Oct3/4, Klf4, and Sox2− have
been linked to cancer and are strikingly overexpressed in the
pancreatic CSC compartment.
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VICE-DIRECTION OF TRANSLATIONAL RESEARCH
MOLECULAR PATHOLOGY PROGRAMME | SteM ceLLS AnD cAnceR GRoUp
RESEARCH HIGHLIGHTS
Figure 2 CAM-PaC strategy. Gathering of (pre-) clinical, histopathological, RNAseq, and metabolic data. Data
integration using a combination of bioinformatics and tailored shRNA library
screens for self-renewal, metastasis and
resistance. Target screen using established in vitro models. Target validation
using RNAi mice. Eventually, we want to
identify novel therapeutic targets and
predictive biomarkers, which would
then be tested in innovative early-phase
clinical trials.
Figure 1 Cancer Stem Cell (CSC) concept. Although the origin of CSCs still
remains elusive for most cancer entities and may actually vary between
patients, distinct populations of CSCs
have already been identified (once the
tumours have been formed). CSCs are
defined by their unlimited self-renewal,
the capability to recapitulate the tumour
heterogeneity (differentiation) and their
exclusive in vivo tumourigenicity. CSCs
are not a single population of uniform
cells; rather, they undergo evolution
through the acquisition of genetic
and epigenetic alternations. Also, the
tumour microenvironment can induce
dramatic changes in their phenotypic
characteristics. For example, a distinct
subpopulation of migrating CSCs, identified by additional CXCR4 expression,
can be detected in the invasive front in
the pancreas as well as in the circulating
blood. Detection of these circulating
CSCs could serve as prognostic and
predictive biomarkers and, even more
importantly, their prospective isolation
as a liquid biopsy should eventually
provide non-invasive access to metastatic CSCs.
∞
∞
Targeting the metabolic Achilles
heel of human pancreatic CSCs
CSCs, actually underwent rapid apoptotic death due to
energy crisis.
Epidemiologic studies have suggested that diabetes mellitus,
particularly type II, is associated with enhanced risk for
pancreatic cancer. Strikingly, in a retrospective analysis,
oral administration of metformin in patients with diabetes
mellitus type II was found to be associated with a reduced
risk for developing pancreatic cancer as well as better
outcome in patients with established pancreatic cancer.
When evaluating metformin for the treatment of pancreatic
cancer in large preclinical studies, we found that the
heterogeneous populations of cancer cells harboured in
primary human pancreatic cancer tissues differed strikingly
in their response to metformin depending on their level
of stemness. While the bulk of more differentiated cancer
cells reacted to metformin treatment with cell cycle arrest,
a subset of cells with distinct stemness features, namely
Our data demonstrate that metformin virtually exhausted
the CSC fraction, but are also consistent with the notion that
non-CSCs do not replenish the pancreatic CSC pool after
termination of metformin treatment. Further metabolic
studies have suggested that pancreatic CSCs actually bear
a highly mitochondrial-dependent metabolic profile,
which is in striking contrast to normal stem cells, but also
distinguishes them from the bulk cancer cells. Metformin
is slowly accumulated 1000-fold within mitochondria
and directly inhibits Complex 1 (NADH dehydrogenase),
thus interfering with this proton gradient across the inner
mitochondrial membrane. Subsequent alteration in the
electron transport chain and oxidative phosphorylation
appear to be particularly lethal for CSCs. Therefore, drugs
such as metformin that target the oxidative mitochondrial
PUBLICATIONS
Sainz B Jr, Heeschen C. (2013). Standing
out from the crowd: cancer stem cells
Scientific RepoRt 2013
∞
in hepatocellular carcinoma. Cancer Cell
23, 431-433.
Hermann PC, Heeschen C (2013). Metastatic Cancer Stem Cells--Quo Vadis?.
∞
Clin Chem 59, 1268-1269.
Trakala M, Fernández-Miranda G, Pérez
de Castro I, Heeschen C, Malumbres M
(2013). Aurora B prevents delayed DNA
∞
replication and premature mitotic exit
by repressing p21 (Cip1). Cell Cycle 12,
1030-1041.
Hermann PC, Trabulo SM, Sainz JrB, Balic
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metabolism represent powerful therapeutic tools for
attacking the CSC pool.
Launching an interdisciplinary research
programme to identify novel targets against CSCs
For many human malignancies, large-scale genomic,
transcriptomic and, to a somewhat lesser degree, proteomic
analyses have been instrumental in establishing a comprehensive
catalogue of molecules that are altered in their structure and/
or abundance in bulk tumours. Far less developed are concepts
and methods for the integration of data from CSCs and their
progenies, and to perform systematic interrogation of gene
functions for CSC features in order to differentiate ‘driver’
alterations − which directly contribute to tumourigenicity and/or
metastasis − from “passenger” alterations, which have minimal
or no influence on CSC biology.
A, Garcia E, Hahn SA, Vandana M, Sahoo
SK, Tunici P, Bakker A, Hidalgo M, Heeschen C (2013). Multimodal treatment
eliminates cancer stem cells and leads
∞
to long-term survival in primary human
pancreatic cancer tissue xenografts.
PLoS One 8, e66371.
Lonardo E, Cioffi M, Sancho P, Sanchez-
SpAniSH nAtionAL cAnceR ReSeARcH centRe, cnio
Therefore, the goal of our new pan-European project CAMPaC is to functionally interrogate transcriptomic data from
a large set of primary human pancreatic CSCs in order to
systematically identify these driver genes/pathways (FIGURE
2). This will be achieved by tailored shRNA screening (~500
pre-specified genes). The obtained shortlist of genes/pathways
(~20 per functional feature) will then be comprehensively
characterised and, if indeed of crucial functional relevance for
the CSC phenotype, further validated as novel CSC targets for
therapeutic intervention. Eventually, a unique collection of
pre-selected and pre-characterised CSC candidate genes will be
selected for systematic functional characterisation using RNAi
mouse models in combination with novel genetically engineered
mouse models of pancreatic cancer. The latter will allow for the
independent temporal control of up to four initiating genetic
events (e.g. 1st hit: KrasG12D/+, 2nd hit: Tp53R172H/+, 3rd hit:
DPC4 shRNA) in a postnatal setting and should more accurately
reflect human disease. s
Ripoll Y, Trabulo SM, Dorado J, Balic A,
Hidalgo M, Heeschen C (2013). Metformin targets the metabolic achilles heel
of human pancreatic cancer stem cells.
∞
PLoS One 8, e76518.
Garcia-Silva S, Frias-Aldeguer J, Heeschen C (2013). Stem cells & pancreatic
cancer. Pancreatology 13, 110-113.
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