Cancer evolution is driven by selection acting on genetic and epigenetic diversity to promote the propagation of the fittest subpopulations. This phenomenon is shaped by the tumor microenvironment which is often characterized by stressful conditions. Epigenetic regulators are frequently mutated during the later stages of tumorigenesis, but the functional impact of their inactivation is poorly understood.
In this thesis, I hypothesize that the disruption of the epigenetic regulatory network increases cell fitness in unfavorable environments and thus is selected over time. Through large-scale fitness assays in various cancer models, I demonstrate that epigenetic deregulation leads to a widespread stress-specific survival advantage. This effect is mediated by mutations in all layers of epigenetic regulation, is shared across different stress conditions and is cancer type independent. Then, I explore various cellular mechanisms that can underlie this stress-specific fitness advantage. Genetic diversity, transcriptional heterogeneity or phenotypic plasticity cannot explain the increased survival under stress, as revealed by a combination of reversible epigenetic inhibition, live-cell imaging and single-cell transcriptomics. On the contrary, epigenetically deregulated cells remain phenotypically inert (less responsive) under stress. Transcriptional profiling of cancer populations in hostile conditions, revealed significant alterations in fitness and growth-related signatures. Disruption of the epigenetic machinery results in a defective stress response, thus decreasing the probability of such cells to surpass a stressed threshold and ultimately die. This defective transcriptional rewiring underpins the inert phenotype that emerges upon epigenetic deregulation.
Collectively, by investigating the effect of inactivating mutations in epigenetic regulators on cell fitness under environmental stress, I propose that phenotypic inertia is the favorable cellular trait that is selected over time. My findings provide a potential explanation for the widespread subclonal mutations affecting epigenetic regulators and have significant implications for cancer evolution.