Cell competition and stem cell parasitism in a basal chordate

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ABSTRACT Cell competition is a process that compares the relative fitness of progenitor cells, resulting in `winners', which contribute further to development, and `losers', which are excluded, and is likely a universal quality control process that contributes to the fitness of an individual. Cell competition may also be involved in cancer, during which cells become `supercompetitors', subsequently outcompeting normal cells for resources and growth. Thus cell competition is a widespread phenomenon that has both developmental and disease relevance. However, the mechanisms underlying cell competition are not well understood. What is a sensor of fitness? Are there common regulatory mechanisms? How do the mechanisms underlying competition break down during disease? We are utilizing the unique biology of a model organism that will allow us to study these questions. Our model is the colonial tunicate, Botryllus schlosseri, which has germline stem cells (GSCs) that have genetically determined competitive phenotypes, with winner cells outcompeting loser cells. We can exploit the natural phenotypic variation present in our lab reared populations to characterize the mechanisms underlying cell competition. We can purify these cells to near homogeneity using FACS, transplant them, and quantify their contribution to gamete development. We have recently found that competitive differences may be in differences in migratory ability, specifically how cells responds to lipid signaling. In Aim 1, we will build upon these recent results, using both in vitro and in vivo assays developed in our lab to dissect the response of GSCs to lipid signaling. In Aim 2, we will take an unbiased approach, characterizing germ cell migration and development using different competitive genotypes developed in our lab, both in situ and during competition, following reciprocal transplantations, and utilize this natural phenotypic variation to pinpoint where competition may occur. Completion of the proposed aims will advance our understanding of the mechanisms which underlie competitive interactions between stem cells, which is becoming increasingly appreciated as a fundamental and conserved process in multicellular development, and may be important for instructing clinical regeneration using stem cells. When inappropriately activated, these competitive mechanisms may also be responsible for escape of normal growth control during cancer progression. Botryllus is a unique organism that allows novel approaches to study conserved molecular mechanisms of cell competition that underlie development, regenerative medicine, and cancer progression, areas of great importance for human health.