Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors
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<sup>+</sup>) and non-irradiated (RT<sup>-</sup>) sites in breast cancer survivors who underwent RT years ago. Here we show that the RT<sup>+</sup> skin has compromised healing capacity and fibroblast functions. Using ATAC-seq, we discover altered chromatin landscapes in RT<sup>+</sup> 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<sup>+</sup> 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.
Authors
- Maria Genander (ORCID: https://orcid.org/0000-0002-2428-8040)
- Xiaowei Bian (ORCID: https://orcid.org/0000-0001-8999-7078)
- Evelien Eenjes (ORCID: https://orcid.org/0000-0001-7108-0659)
- Traimate Sangsuwan (ORCID: https://orcid.org/0000-0003-4051-8376)
- Siamak Haghdoost (ORCID: https://orcid.org/0000-0002-2867-4774)
- Connor A. Bain (ORCID: https://orcid.org/0000-0002-0428-806X)
- Candice Diaz
- Minna Piipponen (ORCID: https://orcid.org/0000-0002-5078-3029)
- Pehr Sommar (ORCID: https://orcid.org/0000-0002-9789-9221)
- Michael L. Crichton (ORCID: https://orcid.org/0000-0002-3683-802X)
- Monica Maselli
- Julie Fradette (ORCID: https://orcid.org/0000-0002-1851-5112)
- Jennifer Geara
- Yongjian Chen (ORCID: https://orcid.org/0000-0002-2930-8450)
- Martin Halle (ORCID: https://orcid.org/0000-0002-6222-956X)
- Jenna L. Cash (ORCID: https://orcid.org/0000-0002-1183-185X)
- Louis Archambault (ORCID: https://orcid.org/0000-0002-6065-3113)
- Zhuang Liu (ORCID: https://orcid.org/0000-0001-8938-0086)
- Lihua Luo (ORCID: https://orcid.org/0000-0002-2129-4226)
- Ning Xu (ORCID: https://orcid.org/0000-0003-4868-3798)
Institutions
- Karolinska University Hospital (SE)
- Stockholm University (SE)
- Karolinska Institutet (SE)
- Heriot-Watt University (GB)
- MRC Centre for Regenerative Medicine (GB)
- Centre for Inflammation Research (GB)
- Université Laval (CA)
- Aliments Bioprocédés Toxicologie Environnements
- University of Edinburgh (GB)
- Université de Caen Normandie (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1038/s41467-024-53295-1
- Citations
- 23
- Primary Topic
- Effects of Radiation Exposure
- Type
- article
- Field-Weighted Citation Impact
- 9.30
Funders
- Université Laval
- Cancerfonden
- Karolinska Institutet
- Stockholms Läns Landsting
- Vetenskapsrådet
- Sigrid Juséliuksen Säätiö
- Svenska Läkaresällskapet
- Strålsäkerhetsmyndigheten
- LEO Fondet
- HudFonden
- Canadian Institutes of Health Research
- Uppsala Multidisciplinary Center for Advanced Computational Science
- Institute of Musculoskeletal Health and Arthritis