Related Experiment Video
Updated: Jun 9, 2025
Establishment of a Robust and Reproducible Model of Radiation-Induced Skin and Muscle Fibrosis
Published on: August 31, 2022
Radiation-induced morphea of the breast - characterization and treatment of fibroblast dysfunction with repurposed
Stephan R Künzel1,2,3,4, Erik Klapproth5, Nick Zimmermann6
1Institute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. stephan.kuenzel@tu-dresden.de.
Abstract:
Radiation-induced morphea (RIM) is a rare complication of radiotherapy presenting as inflammatory fibrosis, most commonly reported in breast cancer patients. As underlying disease mechanisms are not well understood, targeted therapies are lacking. Since fibroblasts are the key mediators of all fibroproliferative diseases, this study aimed to characterize patient-derived fibroblasts to identify therapeutic targets. We studied primary human control and RIM-fibroblasts on a functional and molecular basis, analyzed peripheral blood and tissue samples and conducted, based on our findings, a treatment attempt in one patient. In RIM, we identified a distinct myofibroblast phenotype reflected by increased alpha-smooth-muscle-actin (αSMA) expression, reduced proliferation and migration rates, and overexpression of osteopontin (OPN). Our RNA sequencing identified aberrant Myc activation as a potential disease driver in RIM fibroblasts, similar to previous findings in systemic sclerosis. Treatment with the anti-inflammatory drug mesalazine reversed the myofibroblast phenotype by targeting Myc. Based on these findings, a patient with RIM was successfully treated with mesalazine, resulting in reduced inflammation and pain and tissue softening, while serum OPN was halved. The present study provides a comprehensive characterization of RIM fibroblasts, suggests a disease-driving role for Myc, demonstrates promising antifibrotic effects of mesalazine and proposes OPN as a biomarker for RIM.
Insights
Radiation-induced morphea (RIM) is a rare fibrotic complication of radiotherapy. Targeting Myc with mesalazine reversed fibroblast abnormalities and successfully treated a patient, suggesting a new therapeutic approach.
Area of Science:
- Fibrotic diseases
- Radiotherapy complications
- Dermatology
Background:
- Radiation-induced morphea (RIM) is a rare, poorly understood complication of radiotherapy, often seen in breast cancer patients.
- Current targeted therapies for RIM are lacking due to limited understanding of its underlying disease mechanisms.
- Fibroblasts are central to fibroproliferative diseases, making them key targets for therapeutic intervention.
Purpose of the Study:
- To characterize patient-derived fibroblasts in RIM to identify potential therapeutic targets.
- To investigate the molecular mechanisms driving RIM.
- To evaluate the therapeutic potential of mesalazine in RIM.
Main Methods:
- Functional and molecular characterization of primary human control and RIM-fibroblasts.
- Analysis of peripheral blood and tissue samples from RIM patients.
- RNA sequencing to identify molecular drivers.
- A case study involving mesalazine treatment in one RIM patient.
Main Results:
- RIM fibroblasts exhibit a distinct myofibroblast phenotype with increased alpha-smooth-muscle-actin (αSMA), reduced proliferation/migration, and osteopontin (OPN) overexpression.
- Aberrant Myc activation was identified as a potential driver in RIM fibroblasts.
- Mesalazine treatment reversed the myofibroblast phenotype by targeting Myc.
- A RIM patient treated with mesalazine showed reduced inflammation, pain, tissue softening, and halved serum OPN levels.
Conclusions:
- RIM fibroblasts display a unique myofibroblast phenotype driven by Myc activation.
- Mesalazine demonstrates promising antifibrotic effects by targeting Myc.
- Osteopontin (OPN) may serve as a useful biomarker for RIM.
- This study provides a basis for developing targeted therapies for radiation-induced morphea.
