Abstract
Cutaneous radiation injury is an unintended consequence of radiotherapy for many common cancers and can progress to debilitating radiation-induced skin fibrosis (RISF). Existing radiation injury models do not fully capture the skin toxicities observed in patients, contributing to the lack of efficacious therapies to mitigate RISF. To address this, we developed an ex vivo human skin model that recapitulates the temporal radiation injury and RISF response. Human skin explants (n = 12) subjected to ionizing radiation demonstrated DNA double-stranded breaks and robust p53-driven transcriptional programming of cell cycle arrest, apoptosis, and senescence compared with nonirradiated controls. Irradiated skin also exhibited induction of pro-inflammatory cytokines, epithelial-mesenchymal transition, profibrotic TGF-β1–mediated signaling, and thickened collagen over time. P53 regulators murine double minute 2 (MDM2) and miR-34a were induced after irradiation and may be leveraged to modulate injury response. Notably, RNA-sequencing of postradiotherapy breast skin from patients who had undergone mastectomy showed similar p53, inflammatory, and TGF-β1 signatures as the ex vivo model, supporting its translational relevance. Together, this model provides a platform for identifying biomarkers and testing therapies to prevent or mitigate cutaneous radiation toxicities. Targeting the dynamic p53-driven profibrotic radiation response represents a potentially new therapeutic avenue to improve quality of life for patients after radiotherapy.
Authors
Caroline Dodson, Sophie M. Bilik, Gabrielle DiBartolomeo, Hannah Pachalis, Lindsey G. Siegfried, Jordan A.K. Johnson, Seth R. Thaller, Irena Pastar, Marjana Tomic-Canic, Anthony J. Griswold, Rivka C. Stone
Figure 3
Regulators of p53-mediated DNA damage response.
