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Investigating the mechanisms of cell competition in mammals using in vitro systems 10.17863/CAM.37441 Goschorska, Maja Piddini, Eugenia 000000033901076X Rawlins, Emma Louise 0000000174263792 Cell competition leads to elimination of a viable cell population, by fitter cells. Despite over forty years of research, the molecular mechanisms of competition in mammals are poorly understood. During my PhD I have investigated the mechanisms of competition by exploring an established mammalian cell culture system, in which wild-type MDCK cells eliminate scribble-deficient cells, and I have also developed a novel cell culture system to model mammalian competition. My work contributed to the discovery that scribble-deficient cells are eliminated not by biochemical exchange among cells, but by mechanical compaction. We termed this phenomenon mechanical competition. I employed transcriptional profiling to determine the molecular signature of mechanical losers, and identified activation of p53 signalling as their hallmark. My colleagues and I then demonstrated that elevation of p53 is both necessary and sufficient to trigger mechanical competition. In further investigating the mechanisms of mechanical competition, I found that compaction activates ROCK in scribble-deficient cells, and that this is required for their elimination. Inhibition of Src signalling in mechanical losers also protected them form out-competition, and integrin signalling is another pathway likely involved in mechanical competition. While investigating p53 competition, we observed that p53-high and p53-low cells engage in directional migration, with p53-high cells always at the migrating front. As a side-project, I investigated the role of p53 in directional migration, by exploring an established model with a single leader cell and multiple followers. We established a method to generate multinucleated leaders on demand. By creating leaders from p53-deficient cells, I established that p53 signalling is required for some, but not all multinucleated cells to trigger collective migration, thus implicating p53 signalling in a type of migration involved in wound healing. Finally, I successfully modelled p53-driven mechanical competition in a differentiated primary tracheal epithelial cell culture, thereby establishing a novel system to study mammalian competition, and also proving that p53 competition is conserved between different mammalian epithelia. Considering the involvement of p53, mechanical competition may play a major role in cancer. University of Cambridge 2017-01-04 Thesis Doctoral Doctor of Philosophy (PhD) en Fully funded by the Cambridge Cancer Centre https://www.repository.cam.ac.uk/handle/1810/290214 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/0e8e6c2f-8366-4156-a778-16a3d0d21bf8/download 62e6f0ae3487d4199203bd5c244fa158 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c80755f2-5bd6-4a2a-839a-9d0feb1a5cf3/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ cell competition cell biology p53 cell culture cancer research Scribble