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Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia
journal contributionposted on 2023-01-12, 12:26 authored by Ioannis Loukas, Fabrizio Simeoni, Marta Milan, Paolo Inglese, Harshil Patel, Robert Goldstone, Philip East, Stephanie Strohbuecker, Richard Mitter, Bhavik Talsania, Wenhao Tang, Colin DH Ratcliffe, Erik Sahai, Vahid Shahrezaei, Paola Scaffidi
The evolution of established cancers is driven by selection of cells with enhanced fitness. Subclonal mutations in numerous epigenetic regulator genes are common across cancer types, yet their functional impact has been unclear. Here, we show that disruption of the epigenetic regulatory network increases the tolerance of cancer cells to unfavorable environments experienced within growing tumors by promoting the emergence of stress-resistant subpopulations. Disruption of epigenetic control does not promote selection of genetically defined subclones or favor a phenotypic switch in response to environmental changes. Instead, it prevents cells from mounting an efficient stress response via modulation of global transcriptional activity. This "transcriptional numbness" lowers the probability of cell death at early stages, increasing the chance of long-term adaptation at the population level. Our findings provide a mechanistic explanation for the widespread selection of subclonal epigenetic-related mutations in cancer and uncover phenotypic inertia as a cellular trait that drives subclone expansion.
Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: 10152, Grant title: Scaffidi FC001152) Crick (Grant ID: 10144, Grant title: Sahai FC001144)
adaptationcancer epigeneticschromatin modifiersenvironmental stressmechanisms of cancer evolutionmutationspan-cancerplasticitysubclonaltumor microenvironmentScaffidi FC001152Sahai FC001144CBAS-ackLM-ackFC-ackHP-ackSB-ackBRF-ackChristodoulou, EvangelosKelly, Gavin1109 Neurosciences1112 Oncology and CarcinogenesisOncology & Carcinogenesis