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ONCASYM<br />
<strong>Cancer</strong> stem cells and<br />
asymmetric cell division<br />
Summary<br />
An intense line of current investigation into cancer is based<br />
on the connection between tumourigenesis and stem cell<br />
biology. Some tumours may originate from the transformation<br />
of normal stem cells, at least in the case of blood, breast,<br />
skin, brain, spino-cerebellar and colon cancers. In addition,<br />
tumours may contain ‘cancer stem cells’, rare cells with indefinite<br />
potential for self-renewal that drive tumourigenesis.<br />
Interestingly, the same signalling pathways (TGF-beta/BMP,<br />
Wnt and Notch pathways) appear to regulate self-renewal in<br />
stem cells and cancer cells.<br />
Self-renewal occurs through the asymmetric cell division of<br />
stem cells, which thereby generate a daughter stem cell and<br />
another daughter cell that contributes to populate the developing<br />
organ or the growing tumour. In one of the best<br />
understood asymmetric cell division models, the Drosophila<br />
nervous system, asymmetry is mediated by a biased Notchdependent<br />
signalling event between the two daughter cells.<br />
ONCASYM partners have recently shown:<br />
• that the process of biased signalling during asymmetric<br />
cell division is controlled by endocytosis;<br />
• that tumours can be induced in mutants with altered<br />
stem-cell asymmetric division. In human normal and<br />
cancer stem cells, asymmetric cell division is supposed<br />
to take place, but it has not directly been proven yet.<br />
Furthermore, the role of biased signalling by endocytosis<br />
in these stem cells has not been addressed to date.<br />
The aim of this project is threefold:<br />
• to screen for genes involved in asymmetric cell division<br />
of human cancer stem cells;<br />
• to characterise the asymmetric cell division of these<br />
stem cells by using these candidate genes as markers;<br />
• to study functionally the role of the identifi ed candidate<br />
genes during asymmetric cell division of cancer stem<br />
cells. Our ultimate goal is to untangle the molecular<br />
machinery of cancer stem cell asymmetric division,<br />
thereby providing druggable targets for cancer therapy.<br />
Problem<br />
Cell types within a tumour vary in their ability to form the<br />
whole tumour mass. In fact, only very few cells can give rise<br />
to all cells present in the tumour. These so-called tumour<br />
stem cells have been characterised in a variety of tumours,<br />
including leukaemia, breast cancer and brain tumours. Their<br />
existence challenges conventional tumour therapy, which is<br />
62<br />
Keywords | Drosophila | breast cancer | colorectal cancer | mammospheres | crypt | tissue array | larval neuroblast |<br />
sensory organ precursor |<br />
targeted at destroying rapidly proliferating cells. Stem cells<br />
often proliferate slowly and might not be eliminated by such<br />
therapies, which might explain the high relapse rate observed<br />
for some cancers. Alternative therapies that target stem<br />
cells are not available. This is partly due to our limited understanding<br />
of proliferation control in stem cells and the lack of<br />
appropriate cancer models which mimic the development<br />
of tumours from defi ned stem cell populations.<br />
Aim<br />
The goal of this project is to develop new therapeutic<br />
strategies that target tumour stem cells. Stem cells are<br />
characterised by their ability to divide asymmetrically and<br />
thereby form self-renewing and diff erentiating daughter<br />
cells at the same time. Even a slight change in the balance<br />
between these two cell types could dramatically increase<br />
the number of daughter cells created by a stem cell and<br />
thereby contribute to tumour formation.<br />
Expected results<br />
In our project we plan:<br />
• to discover the genes involved in asymmetric cell division<br />
and tumour suppression in normal and malignant<br />
stem cells, using Drosophila as a model system, and to<br />
fi nd their human and mouse homologues;<br />
• to use this candidate gene list to fi nd markers for the<br />
identifi cation of normal and cancer stem cells in the<br />
mammary gland and the intestinal crypts and use these<br />
markers to image the asymmetric cell division event.<br />
Potential applications<br />
We will directly translate the acquired knowledge into the<br />
clinical practice.<br />
• We plan to validate the newly identifi ed ‘stemness’ signature<br />
as a clinical tool for genomic grading and<br />
prognostic evaluation. This task will be initially accomplished<br />
by retrospectively performing meta-analysis,<br />
using the currently available public databases as well as<br />
the wide collection of cases from our tumour registry.<br />
• Tissue microarrays will be used to further validate the<br />
relevance of candidate ‘stemness’ genes to the diagnostic<br />
routine, by establishing their predictive strength in<br />
relation to the common clinical-prognostic parameters.<br />
• Prospectively, the identifi ed ‘stemness’ genes will be<br />
introduced as ‘biomarkers’ for the clinical and prognostic<br />
evaluation of cancer patients enrolled in ad hoc clinical<br />
trials at the European Institute of Oncology, even<br />
including their use in the procedure of the sentinel node<br />
in order to identify the presence of stem cells in<br />
metastasis.<br />
CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
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