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 L. Crichton, Jenna L. Cash, Louis Archambault, Siamak Haghdoost, Julie Fradette, Pehr Sommar, Martin Halle, Ning Xu
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.