Blocking THBS1 with antibodies may heal radiotherapy induced skin injury
In a recently published study, researchers at Karolinska Institutet and KI University Hospital show that radiotherapy (RT) creates an "epigenetic memory" in skin fibroblasts which impairs skin healing in cancer survivors. They also found that by targeting this memory with antibodies the damage could be reversed. This finding can lead to new therapies for both preventing and treating RT-induced skin issues.
Radiotherapy (RT) can cause not only short-term skin damage but also long-lasting effects like chronic ulcers and fibrosis, which may appear years after treatment and severely affect cancer survivors' quality of life.
While the causes of these long-term complications have been unclear, the researchers have now shown that RT leaves an "epigenetic memory" in skin fibroblasts, altering their ability to heal wounds. This memory causes fibroblasts to overproduce a protein called THBS1, which disrupts their function.
Interestingly, the researchers also found that by blocking these THBS1 with antibodies the damage could be reversed. These findings can potentially lead to the development of new therapies for preventing and treating RT-induced skin issues and thereby improve the quality of life for many cancer survivors.
Methodology
The researchers studied 46 breast cancer survivors who previously received radiotherapy and collected skin biopsies from both irradiated and non-irradiated areas during reconstructive surgeries.
Further, they investigated fibroblast activity and chromatin changes using advanced methods like ATAC-seq, RNA-seq, single-cell RNA-seq, and single-cell multiome ATAC+RNA -seq.
The researchers also tested a topical treatment on human ex vivo wound models, exploring how targeting THBS1 could enhance healing.
The next step
The next step is to further investigate the therapeutic potential of anti-THBS1 antibodies and inhibitors of CD47 - a receptor of THBS1 in clinical settings, to evaluate their effectiveness in preventing and treating late-onset skin complications of radiotherapy in cancer survivors.
The researchers will also explore the broader implications of epigenetic memory in other tissues and diseases, aiming to better understand how this process can be leveraged to prevent or treat diseases.
Publication
Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors.
Bian X, Piipponen M, Liu Z, Luo L, Geara J, Chen Y, Sangsuwan T, Maselli M, Diaz C, Bain CA, Eenjes E, Genander M, Crichton M, Cash JL, Archambault L, Haghdoost S, Fradette J, Sommar P, Halle M, Xu Landén N
Nat Commun 2024 Oct;15(1):9286.
Last author: Ning Xu Landén, Department of Medicine, Solna.
Picture
The research team: Martin Halle, Xiaowei Bian, Ning Xu Landén, Pehr Sommar. Missing: Minna Piipponen. Photo: Jennifer Geara.