Objective
The “Cancer Stem Cell (CSC) Hypothesis” postulates that the capacity to maintain tumour growth is owned by rare cancer cells, the CSCs, endowed with self-renewal properties. This hypothesis implies that CSCs must be eliminated to achieve cancer cure. Nevertheless, direct proof is still lacking, and recent findings challenge our concepts of CSCs, showing the limits of the CSC-defining assay (transplantation) and suggesting that CSC-identity might be context-dependent. We found two properties of CSCs self-renewal that are indispensable for the maintenance of an expanding CSC-pool and tumour growth: increased frequency of symmetric divisions, due to inactivation of the p53 tumour suppressor, and increased replicative potential, due to up-regulation of the cell-cycle inhibitor p21. We will now investigate: i) How loss of p53 in tumours leads to expansion of the CSC pool, by testing the hypothesis that p53-loss activates the Myc oncogene which induces CSC-reprogramming of differentiated cancer cells. ii) Whether p53-independent pathways are also implicated, by in vivo shRNA screens of primary tumours or normal progenitors to identify pathways involved, respectively, in CSC self-renewal or inhibition of SC-reprogramming. iii) How p21-induced cell-cycle arrest protects CSCs from self-renewal exhaustion, by investigating regulation of cell-cycle recruitment of quiescent CSCs. iv) Whether activation of p21 in CSCs induces a mutator phenotype, due to its ability to activate DNA repair, by investigating mechanisms of DNA-damage, mutation rates, and relevance of CSC mutations for development of chemoresistance. We will test self-renewal functions in a transplantation-independent assay, based on tumour re-growth in vivo after cytotoxic treatments and “clonal tracking” of re-growing tumours (using barcoded lentiviral libraries). Our long-term goal is the identification of CSC-specific targets that could be used to create the basis for CSC-specific pharmacological intervention.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciences biological sciences genetics DNA
- medical and health sciences medical biotechnology cells technologies stem cells
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
- medical and health sciences clinical medicine transplantation
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
ERC-2013-ADG
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Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Host institution
20121 Milano
Italy
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.