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Transcriptome-wide profiling of human stromal cells in mouse xenografts during preclinical treatment involving chemotherapy and/or the novel senomorphic agent dihydromyricetin

ABSTRACT: Aging is a major risk factor for the vast majority of geriatric conditions, including various malignancies. Although cancer development can be generally attributed to the accumulation of genetic mutations, biological processes associated with aging also hold the potential to regulate cancer progression. Cellular senescence is a cell state characterized by a permanent cell cycle arrest. Senescent cells tend to accumulate with aging, exhibit pro-inflammatory activities (SASP) and promote cancer development. However, as the effect of cellular senescence on cancer progression is heterogeneous and complicated, detailed mechanisms remain to be unraveled. Fortunately, senescent cells can be eliminated by several strategies, a situation that allows to prevent incidence of chronic disorders and prolong healthspan of mammalians. Strategies involving senolytics, which can selectively remove senescent cells by targeting the SCAP, have recently emerged as a prominent and competent solution to ameliorate diverse age-related pathologies. Achieving the goal using synthetic or natural agents (the latter more preferred in clinical settings) would generate a tremendous impact on the quality of life. Here, we test the potential of dihydromyricetin (DMY), a bioactive compound extracted from Salvia miltiorrhiza, in targeting senescent cells through inhibiting the SASP in a preclinical regimen. This study demonstrates the efficacy of DMY in downregulating the SASP expression and reducing the influence of senescent stromal cells in treatment-damaged tumor microenvironment and provides a strong rationale for its future development in anti-aging pipelines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291050 | GEO | 2026/01/13

REPOSITORIES: GEO

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Project description:Cellular senescence is a stable proliferation arrest in response to stress, associated with an altered secretory pathway (Senescence Associated Secretory Phenotype (SASP)). Senescence-associated proliferation arrest and the SASP are thought to act in concert to promote tumor suppression and tissue aging. While chromatin regulation and down regulation of lamin B1 have been implicated as effectors of cell senescence, functional interactions between them are poorly understood. We compared the genome-wide distributions of H3K4me3 and H3K27me3 between proliferating and senescent primary human cells and found dramatic differences, including large-scale domains of H3K4me3- and H3K27me3-enriched “mesas” and H3K27me3-depleted “canyons” in senescent cells. Senescent mesas form at the sites of lamin B1-associated domains (LADs) in proliferating cells. Mesas also overlap with regions that exhibit DNA hypomethylation in cancer, suggesting that chromatin changes in pre-malignant senescent cells foreshadow epigenetic changes in cancer. Proliferating fibroblasts from Hutchinson-Gilford Progeria Syndrome patients expressing mutant lamin A (progerin) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence and tissue aging. In contrast, canyons form mostly in between LADs and are enriched in genes, gene promoters and enhancers. Strikingly, H3K27me3 loss in canyons is correlated with upregulation of key senescence genes, including genes comprising the SASP, indicating a link between global changes in chromatin structure and local regulation of gene expression. Finally, premature reduction of lamin B1 in midlife proliferating cells triggers formation of senescence-associated mesas and canyons and accelerated senescence. Together, our data illustrate a profound reorganization of chromatin during senescence, and suggest that down regulation of lamin B1 in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging and cancer.

Project description:Cellular senescence is a stable proliferation arrest in response to stress, associated with an altered secretory pathway (Senescence Associated Secretory Phenotype (SASP)). Senescence-associated proliferation arrest and the SASP are thought to act in concert to promote tumor suppression and tissue aging. While chromatin regulation and down regulation of lamin B1 have been implicated as effectors of cell senescence, functional interactions between them are poorly understood. We compared the genome-wide distributions of H3K4me3 and H3K27me3 between proliferating and senescent primary human cells and found dramatic differences, including large-scale domains of H3K4me3- and H3K27me3-enriched "mesas" and H3K27me3-depleted "canyons" in senescent cells. Senescent mesas form at the sites of lamin B1-associated domains (LADs) in proliferating cells. Mesas also overlap with regions that exhibit DNA hypomethylation in cancer, suggesting that chromatin changes in pre-malignant senescent cells foreshadow epigenetic changes in cancer. Proliferating fibroblasts from Hutchinson-Gilford Progeria Syndrome patients expressing mutant lamin A (progerin) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence and tissue aging. In contrast, canyons form mostly in between LADs and are enriched in genes, gene promoters and enhancers. Strikingly, H3K27me3 loss in canyons is correlated with upregulation of key senescence genes, including genes comprising the SASP, indicating a link between global changes in chromatin structure and local regulation of gene expression. Finally, premature reduction of lamin B1 in midlife proliferating cells triggers formation of senescence-associated mesas and canyons and accelerated senescence. Together, our data illustrate a profound reorganization of chromatin during senescence, and suggest that down regulation of lamin B1 in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging and cancer.

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Transcriptome-wide profiling of human stromal cells in mouse xenografts during preclinical treatment involving chemotherapy and/or the novel senomorphic agent dihydromyricetin

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