Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia

Model organisms Chemical Biology & High Throughput 0301 basic medicine 570 Human Biology & Physiology 0303 health sciences Stem Cells Genome Integrity & Repair 610 Gene Expression Cell Biology Tumour Biology Imaging 3. Good health 03 medical and health sciences Phenotype Neoplasms Mutation Humans Cell Cycle & Chromosomes Genetics & Genomics Computational & Systems Biology
DOI: 10.1016/j.ccell.2022.10.002 Publication Date: 2022-11-03T14:26:45Z
ABSTRACT
The evolution of established cancers is driven by selection 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 the regulatory network increases tolerance to unfavorable environments experienced within growing tumors promoting emergence stress-resistant subpopulations. Disruption control does not promote genetically defined subclones or favor a phenotypic switch response environmental changes. Instead, it prevents from mounting an efficient stress via modulation global transcriptional activity. This "transcriptional numbness" lowers probability cell death at early stages, increasing chance long-term adaptation population level. Our findings provide mechanistic explanation for widespread subclonal epigenetic-related and uncover inertia as cellular trait drives subclone expansion.
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