Ribosome mutant-induced Cell Competition: from mechanisms to identification of cancer vulnerabilities

Cell competition is a fundamental process that removes suboptimal cells in tissues. The best studied example is 'Minute cell competition', a type of competition where cells mutated in ribosome protein genes (RPGs) are eliminated by surrounding non-mutated cells. Understanding how Minute competition works could be key to tackle cancer, as cancer cells are often mutated in RPGs. We will: a) Elucidate the mechanisms controlling Minute cell competition, by establishing the first mammalian cell assays enabling its study in vitro. b) Identify how Nrf2 - a key gene we previously implicated in Minute cell competition - causes cell elimination, using Drosophila. Excitingly, we recently discovered that many Nrf2 effectors are metabolic enzymes. Building on this discovery we will identify metabolites that modulate cell competition which could be used therapeutically. c) Use human cancer bioinformatics and Drosophila genetics to understand why RPG-mutant human cancers evade being 'out-competed' by healthy cells in tumours.