Understanding the mechanisms of Cell Competition and its role in tissue biology (360G-Wellcome-205010_Z_16_Z)

Cell competition is increasingly recognized as playing a key role in selecting the cellular composition of tissues, both in health and diseases such as cancer. My proposed research aims to advance our understanding of the mechanisms of cell competition and how it impacts on adult tissue biology, to advance our fundamental understanding of this biomedically-relevant process and learn how to harness it for therapeutics. Building on my group’s recent discoveries and methodological advances, I will use an integrated strategy combining in vitro and in vivo approaches to: 1) Elucidate how the oxidative stress response, which we found marks cells as ‘losers’ for competitive elimination, triggers cell competition in Drosophila. 2) Elucidate another link we discovered between aberrant autophagy in ‘loser’ cells and cell competition, in Drosophila. 3) Characterize the molecular mechanisms behind our discovery of p53-induced cell competition, using a CRISPR-based genomic screen in mammalian cultured cells. 4) Investigate the impact of cell competition on human adult tissue biology, using human primary keratinocytes and p53 competition-inducing mutations. 5) Carry out targeted proof-of-principle experiments to investigate for the first time whether cell competition can be exploited to improve tissue engraftment and repopulation in vivo, using the mouse airway.