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Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors
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Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors
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Journal Article
Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors
2024
Overview
Radiotherapy (RT), a common cancer treatment, unintentionally harms surrounding tissues, including the skin, and hinders wound healing years after treatment. This study aims to understand the mechanisms behind these late-onset adverse effects. We compare skin biopsies from previously irradiated (RT
+
) and non-irradiated (RT
−
) sites in breast cancer survivors who underwent RT years ago. Here we show that the RT
+
skin has compromised healing capacity and fibroblast functions. Using ATAC-seq, we discover altered chromatin landscapes in RT
+
fibroblasts, with
THBS1
identified as a crucial epigenetically primed wound repair-related gene. This is further confirmed by single-cell RNA-sequencing and spatial transcriptomic analysis of human wounds. Notably, fibroblasts in both murine and human post-radiation wound models show heightened and sustained
THBS1
expression, impairing fibroblast motility and contractility. Treatment with anti-THBS1 antibodies promotes ex vivo wound closure in RT
+
skin from breast cancer survivors. Our findings suggest that fibroblasts retain a long-term radiation memory in the form of epigenetic changes. Targeting this maladaptive epigenetic memory could mitigate RT’s late-onset adverse effects, improving the quality of life for cancer survivors.
The molecular mechanisms underlying the late-onset adverse effects of radiotherapy remain to be explored. Here, the authors observe compromised wound healing capacity in irradiated skin from breast cancer survivors and highlight THBS1 as a key epigenetically primed wound repair-related gene.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/21
/ 13/51
/ 13/89
/ 14/19
/ 45/15
/ 45/23
/ 45/77
/ 45/91
/ Animals
/ Biopsy
/ Breast Neoplasms - pathology
/ Breast Neoplasms - radiotherapy
/ Cancer
/ Epigenesis, Genetic - radiation effects
/ Female
/ Fibroblasts - radiation effects
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Radiotherapy - adverse effects
/ Science
/ Skin
/ Survival
