Subclonal mutations in epigenetic regulators bring fitness in times of stress

Article Oncology

Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia

Ioannis Loukas et al.

Summary: 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.

CANCER CELL (2023)

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Article Multidisciplinary Sciences

Non-genetic determinants of malignant clonal fitness at single-cell resolution

Katie A. Fennell et al.

Summary: Studies have shown that malignant clonal dominance is a cell-intrinsic and heritable property facilitated by the repression of antigen presentation and increased expression of the secretory leukocyte peptidase inhibitor gene (Slpi). Increased transcriptional heterogeneity enables clonal fitness in diverse tissues and immune microenvironments, as well as in the context of clonal competition between genetically distinct clones. Leukemia stem cells (LSCs) display heritable clone-intrinsic properties of high and low clonal output, which contribute to the overall tumor mass.

NATURE (2022)

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Article Biochemistry & Molecular Biology

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Stefan C. Dentro et al.

Summary: By extensively characterizing intra-tumor heterogeneity (ITH) across 2,658 cancer samples spanning 38 cancer types, this study found evidence of distinct subclonal expansions in nearly all informative samples, with frequent branching relationships between subclones. Positive selection of subclonal driver mutations was observed across most cancer types, indicating the importance of ITH and its drivers in tumor evolution.

CELL (2021)

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Article Biochemistry & Molecular Biology