Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors

Xiaowei Bian, Minna Piipponen, Zhuang Liu, Lihua Luo, Jennifer Geara, Yongjian Chen, Traimate Sangsuwan, Monica Maselli, Candice Diaz, Connor A. Bain, Evelien Eenjes, Maria Genander, Michael Crichton, Jenna L. Cash, Louis Archambault, Siamak Haghdoost, Julie Fradette, Pehr Sommar, Martin Halle () and Ning Xu Landén ()
Additional contact information
Xiaowei Bian: Karolinska Institutet
Minna Piipponen: Karolinska Institutet
Zhuang Liu: Karolinska Institutet
Lihua Luo: Karolinska Institutet
Jennifer Geara: Karolinska Institutet
Yongjian Chen: Karolinska Institutet
Traimate Sangsuwan: Stockholm University
Monica Maselli: Karolinska Institutet
Candice Diaz: Centre de recherche en organogénèse expérimentale de l’Université Laval / LOEX
Connor A. Bain: Heriot-Watt University
Evelien Eenjes: Karolinska Institutet
Maria Genander: Karolinska Institutet
Michael Crichton: Heriot-Watt University
Jenna L. Cash: University of Edinburgh
Louis Archambault: Université Laval/Centre de recherche du CHU de Québec
Siamak Haghdoost: Stockholm University
Julie Fradette: Centre de recherche en organogénèse expérimentale de l’Université Laval / LOEX
Pehr Sommar: Karolinska University Hospital
Martin Halle: Karolinska University Hospital
Ning Xu Landén: Karolinska Institutet

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53295-1

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