Functional Cooperation between p53 and MYC in Cancer-Associated Cell Competition

Cell competition is a mechanism conserved from Drosophila to mammals, based on the comparison of relative fitness between neighbouring cells, leading to the apoptotic elimination of the weakest. Several molecules are involved in these competitive interactions: in particular, cells expressing high levels of MYC grow at the expense of surrounding cells. In Drosophila epithelia, MYC-Mediated Cell Competition5 (MMCC) selects cells undergoing clonal expansion, and p53 function is necessary in MYC-overexpressing cells to sustain their competitive advantage. Malignant cells often upregulate MYC and results obtained in our lab suggest that MMCC can shape tumour expansion and evolution. p53 is one of the most frequently mutated genes in human cancers, with both loss and gain of function mutations playing roles in carcinogenesis. Through IHC analysis on several kinds of human carcinomas, in vitro co-culture assays and Drosophila experiments, we observed that loss of p53 in the winner cells is sufficient to make them unable to grow, thus suggesting a functional cooperation between MYC and p53 in cancer-associated MMCC. Our results show an oncogenic side of the p53 wild-type protein that appears to help shape cancer progression through selection of the most competitive cells.