Objectif 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. Champ scientifique natural sciencesbiological sciencesgeneticsDNAmedical and health sciencesmedical biotechnologycells technologiesstem cellsnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologymedical and health sciencesclinical medicinetransplantation Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) ERC-AG-LS4 - ERC Advanced Grant - Physiology, Pathophysiology and Endocrinology Appel à propositions ERC-2013-ADG Voir d’autres projets de cet appel Régime de financement ERC-AG - ERC Advanced Grant Institution d’accueil ISTITUTO EUROPEO DI ONCOLOGIA SRL Contribution de l’UE € 2 500 000,00 Adresse VIA FILODRAMMATICI 10 20121 Milano Italie Voir sur la carte Région Nord-Ovest Lombardia Milano Type d’activité Private for-profit entities (excluding Higher or Secondary Education Establishments) Contact administratif Ilaria Foti (Ms.) Chercheur principal Pier Giuseppe Pelicci (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire ISTITUTO EUROPEO DI ONCOLOGIA SRL Italie Contribution de l’UE € 2 500 000,00 Adresse VIA FILODRAMMATICI 10 20121 Milano Voir sur la carte Région Nord-Ovest Lombardia Milano Type d’activité Private for-profit entities (excluding Higher or Secondary Education Establishments) Contact administratif Ilaria Foti (Ms.) Chercheur principal Pier Giuseppe Pelicci (Prof.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée