Skip to main content

Inside mechanisms sustaining cancer stem cells

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.

Field of science

  • /medical and health sciences/medical biotechnology/cells technologies/stem cells
  • /medical and health sciences/clinical medicine/transplantation
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/clinical medicine/oncology/cancer

Call for proposal

ERC-2013-ADG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

ISTITUTO EUROPEO DI ONCOLOGIA SRL
Address
Via Filodrammatici 10
20121 Milano
Italy
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
EU contribution
€ 2 500 000
Principal investigator
Pier Giuseppe Pelicci (Prof.)
Administrative Contact
Ilaria Foti (Ms.)

Beneficiaries (1)

ISTITUTO EUROPEO DI ONCOLOGIA SRL
Italy
EU contribution
€ 2 500 000
Address
Via Filodrammatici 10
20121 Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Principal investigator
Pier Giuseppe Pelicci (Prof.)
Administrative Contact
Ilaria Foti (Ms.)