Cell Competition in Development and Homeostasis

A process of cell competition can remove cells that differ genetically from neighboring cells in the same tissues. Cell competition helps to eliminate sporadic aneuploid cells that have abnormal chromosome numbers. Aneuploidy contributes to almost all carcinogenesis and is a hallmark of aging, contributing to cellular senescence. The current project investigates the mechanisms by which genes that encode ribosomal proteins, by virtue of their wide distribution in the genome and stoichiometric requirement for ribosome biogenesis, are used as sensors for altered cellular chromosome content, using fruitflies as a genetic model system. Importantly, cells with single mutations in ribosomal protein genes can also be recognized and removed from developing tissues by the process of cell competition with nearby normal cells, related to the elimination of aneuploid cells. This project will further define the molecular mechanisms of cell competition pathways by gain and loss of function genetics targeted specifically to aneuploid cells within otherwise normal tissues, and characterize the alterations in gene expression that result from cell competition on a single cell level. The relationship of specific chromosome gains and losses to tumor formation will be defined. The mechanisms whereby the p53 protein protects the genome from progressive genome damage, and the route by which genomic changes accumulate in the progression towards cancer, will be elucidated. These studies aim to define the molecular basis for the cellular recognition and elimination of aneuploid cells in developing tissues, its role in maintaining genome integrity at the tissue level by selection against abnormal cells, and its role in tumor surveillance and the development of cancers.