Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors
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 irradi...
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| Format: | Article |
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53295-1 |
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| author | 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 Ning Xu Landén |
| author_facet | 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 Ning Xu Landén |
| author_sort | Xiaowei Bian |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-effdd052ea744da69203c471c4031c14 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-effdd052ea744da69203c471c4031c142025-08-20T02:18:33ZengNature PortfolioNature Communications2041-17232024-10-0115112010.1038/s41467-024-53295-1Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivorsXiaowei Bian0Minna Piipponen1Zhuang Liu2Lihua Luo3Jennifer Geara4Yongjian Chen5Traimate Sangsuwan6Monica Maselli7Candice Diaz8Connor A. Bain9Evelien Eenjes10Maria Genander11Michael Crichton12Jenna L. Cash13Louis Archambault14Siamak Haghdoost15Julie Fradette16Pehr Sommar17Martin Halle18Ning Xu Landén19Dermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska InstitutetDermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska InstitutetDermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska InstitutetDermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska InstitutetDermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska InstitutetDermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska InstitutetDepartment of Molecular Biosciences, The Wenner-Gren Institute, Stockholm UniversityDermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska InstitutetCentre de recherche en organogénèse expérimentale de l’Université Laval / LOEXInstitute of Mechanical, Process and Energy Engineering, School of Engineering and Physical Sciences, Heriot-Watt UniversityDepartment of Cell and Molecular Biology, Karolinska InstitutetDepartment of Cell and Molecular Biology, Karolinska InstitutetInstitute of Mechanical, Process and Energy Engineering, School of Engineering and Physical Sciences, Heriot-Watt UniversityCentre for Inflammation Research, Institute for Regeneration and Repair, 4–5 Little France Drive, University of EdinburghDepartment of Physics, Université Laval/Centre de Recherche sur le Cancer, Université Laval/Centre de recherche du CHU de QuébecDepartment of Molecular Biosciences, The Wenner-Gren Institute, Stockholm UniversityCentre de recherche en organogénèse expérimentale de l’Université Laval / LOEXDepartment of Plastic and Reconstructive Surgery, Karolinska University HospitalDepartment of Plastic and Reconstructive Surgery, Karolinska University HospitalDermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska InstitutetAbstract 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.https://doi.org/10.1038/s41467-024-53295-1 |
| spellingShingle | 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 Ning Xu Landén Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors Nature Communications |
| title | Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors |
| title_full | Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors |
| title_fullStr | Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors |
| title_full_unstemmed | Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors |
| title_short | Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors |
| title_sort | epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors |
| url | https://doi.org/10.1038/s41467-024-53295-1 |
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