Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia

• DOI: 10.1016/j.ccell.2022.10.002
• Publication Date: 2022-11-03T14:26:45Z
• Authors: Ioannis Loukas; Fabrizio Simeoni; Marta Milan; Paolo Inglese; Harshil Patel; Robert Goldstone; Philip East; Stephanie Strohbu...; Richard Mitter; Bhavik Talsania; Wenhao Tang; Colin D.H. Ratcliffe; Erik Sahai; Vahid Shahrezaei; Paola Scaffidi
• Keywords: 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

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.