Epigenetic Disruption Enables Cancer Cells to Resist Environmental Stress

Cancer evolution is driven in part by the selection of cells with genetic alterations that influence fitness and enhance the ability to overcome environmental stress. Although human tumors commonly harbor subclonal mutations in genes involved in epigenetic regulation, the impacts of these alterations on cancer cell fitness are not completely understood, with recurrent subclonal mutations being difficult to identify. To address this, Loukas, Simeoni, and colleagues profiled the mutation status of human tumors from multiple pan-cancer datasets, focusing on genes involved in chromatin remodeling, genome topology, histone modifiers, and DNA modifiers. No individual genes were particularly affected by recurrent subclonal mutations, and subclonal loss-of-function mutations were prevalent across all categories, with evidence indicating the positive selection of subclones characterized by a disrupted epigenetic regulatory network. To understand how these widespread alterations contribute to fitness, a panel of epigenetic regulators was inactivated via CRISPR–Cas9 in cell lines derived from patient-derived xenograft models of non–small cell lung cancer and melanoma, followed by exposure to environmental stress via glutamine deprivation. Notably, inactivation of many epigenetic regulators enhanced stress-specific fitness by increasing the frequency of cells that survive shortly after stress. Cancer cells harboring knockout of genes such as EZH2 not only were able to outgrow control cells when cocultured under stress conditions in vitro, but they also outcompeted control cells in vivo, specifically in intratumoral regions of limited nutrient availability. Compared with control cells that initiated a stress-responsive transcriptional and metabolic shift, epigenetically disrupted cells appeared to display phenotypic inertia, minimally inducing stress-responsive genes while maintaining a state of high oxidative phosphorylation upon nutrient deprivation. Moreover, epigenetically disrupted cells did not undergo genome-wide changes in transcriptional burst frequency in response to stress, suggesting that the resulting “transcriptional numbness” may increase the ability to evade cell death at early stages and allow for long-term adaptation. In summary, this study uncovers a process by which epigenetic disruption enhances fitness and promotes subclonal expansion.

Loukas I, Simeoni F, Milan M, Inglese P, Patel H, Goldstone R, et al. Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia. Cancer Cell 2022 Nov 3 [Epub ahead of print].

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