ELUCIDATING MECHANISMS OF CELL COMPETITION DURING DEVELOPMENT

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Project Summary The goal of this proposal is to understand how cell competition regulates tissue growth during development and how such mechanisms can be subverted during diseases like cancer. Our lab and other labs have shown that genetic heterogeneity between neighboring populations provokes competitive interactions between them, resulting in the selective elimination of the weaker population (the losers) and the expansion of the stronger one (the winners). During classical cell competition wild-type cells eliminate viable but sub-optimal cells. This type of cell competition functions as a quality control mechanism to selectively remove suboptimal cells from a tissue. During super-competition, cells with higher levels of oncogenes like STAT and Myc kill their wild-type neighbors. Super-competition functions during cancer progression and metastasis. While competitive interactions are conserved and are increasingly well documented, the mechanisms regulating the elimination of the weaker cells or the expansion of the stronger cells are poorly understood. Through next-generation sequencing, we identified two soluble stress-responsive factors that are produced by STAT winners and that promote their competitive fitness. Here, we will test the roles of these factors in cell competition. Aim 1 is focused on the role of the damage-response pathway in disadvantaging losers or increasing winner fitness in super- competition. Aim 2 will test the role of extracellular reactive oxygen species in killing losers and/or boosting winner function in both classical cell competition and super-competition. We envision that our studies will elucidate molecular and cellular events employed by pre-cancerous cells to establish themselves within a tissue and that might be operative when these cells progress into fully neoplastic lesions.