| Summary: | <p>Colorectal cancer harbours significant intratumoral heterogeneity. Yet, while intratumoural heterogeneity may be readily observed, events which give rise to heterogeneity, as well as an understanding of the molecular effects arising from interactions between clonal populations in each cancer’s unique milieu of heterogeneity, remain elusive. I use <em>FBXW7</em> as the starting point in two separate but related themes. In the first theme, colorectal cancer cell lines are used to model the effect of <em>FBXW7</em> mutations on neighbouring <em>FBXW7</em> wildtype cells. I demonstrate that wildtype cells may acquire phenotypic characteristics present in mutant cells owing from proteins arising from the secretome of mutant cells. In the second theme, I investigate the role of <em>FBXW7</em> present in phenotypically normal tissue using gene editing in patient derived human colon organoids. Here, I demonstrate that early <em>FBXW7</em> mutations result in a more restricted whole genome chromosome accessibility, abrogating the effects of later-acquired cancer driver mutations such as <em>APC</em>. In addition, I demonstrate that an early <em>FBXW7</em> mutation can result in fetal reprogramming. In this way, <em>FBXW7</em> mutations acquired in phenotypically normal tissue appear to be protective in a human colonic model of early colorectal cancer. Taken together, my experiments bear significant implications on understanding colorectal cancer intratumoural heterogeneity. These results suggest that characterising molecular interactions in intra-cancer clonal populations may lead to a deeper understanding of phenotypic characteristics relevant to that cancer. The results also suggest that early events could forestall the generation of heterogeneity and be potentially protective of cancer development. Here, I use <em>FBXW7</em> as an exemplar mutation to generate implications which may be validated using other genes, and in other types of cancer.</p>
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