Radiation-induced morphea of the breast – characterization and treatment of fibroblast dysfunction with repurposed mesalazine
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-10-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-024-74206-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850136673941192704 |
|---|---|
| author | Stephan R. Künzel Erik Klapproth Nick Zimmermann Susanne Kämmerer Mario Schubert Karolina Künzel Maximilian Hoffmann Stephan Drukewitz Anne Vehlow Jiri Eitler Marieke Arriens Jessica Thiel Romy Kronstein-Wiedemann Maximiliane Tietze Stefan Beissert Bertold Renner Ali El-Armouche Claudia Günther |
| author_facet | Stephan R. Künzel Erik Klapproth Nick Zimmermann Susanne Kämmerer Mario Schubert Karolina Künzel Maximilian Hoffmann Stephan Drukewitz Anne Vehlow Jiri Eitler Marieke Arriens Jessica Thiel Romy Kronstein-Wiedemann Maximiliane Tietze Stefan Beissert Bertold Renner Ali El-Armouche Claudia Günther |
| author_sort | Stephan R. Künzel |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ca14d9c2e1744a85acf698b849bb68f5 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-ca14d9c2e1744a85acf698b849bb68f52025-08-20T02:31:03ZengNature PortfolioScientific Reports2045-23222024-10-0114111710.1038/s41598-024-74206-wRadiation-induced morphea of the breast – characterization and treatment of fibroblast dysfunction with repurposed mesalazineStephan R. Künzel0Erik Klapproth1Nick Zimmermann2Susanne Kämmerer3Mario Schubert4Karolina Künzel5Maximilian Hoffmann6Stephan Drukewitz7Anne Vehlow8Jiri Eitler9Marieke Arriens10Jessica Thiel11Romy Kronstein-Wiedemann12Maximiliane Tietze13Stefan Beissert14Bertold Renner15Ali El-Armouche16Claudia Günther17Institute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität DresdenInstitute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität DresdenDepartment of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität DresdenInstitute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität DresdenInstitute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität DresdenInstitute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität DresdenInstitute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität DresdenInstitute of Human Genetics, University of Leipzig Medical CenterOncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität DresdenInstitute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbHInstitute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbHInstitute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbHInstitute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbHInstitute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbHDepartment of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität DresdenInstitute for Clinical Pharmacology, Faculty of Medicine Carl Gustav Carus, Technische Universität DresdenInstitute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität DresdenDepartment of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität DresdenAbstract 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.https://doi.org/10.1038/s41598-024-74206-wFibrosisMorpheaDrug repurposingBreast cancerMesalazine |
| spellingShingle | Stephan R. Künzel Erik Klapproth Nick Zimmermann Susanne Kämmerer Mario Schubert Karolina Künzel Maximilian Hoffmann Stephan Drukewitz Anne Vehlow Jiri Eitler Marieke Arriens Jessica Thiel Romy Kronstein-Wiedemann Maximiliane Tietze Stefan Beissert Bertold Renner Ali El-Armouche Claudia Günther Radiation-induced morphea of the breast – characterization and treatment of fibroblast dysfunction with repurposed mesalazine Scientific Reports Fibrosis Morphea Drug repurposing Breast cancer Mesalazine |
| title | Radiation-induced morphea of the breast – characterization and treatment of fibroblast dysfunction with repurposed mesalazine |
| title_full | Radiation-induced morphea of the breast – characterization and treatment of fibroblast dysfunction with repurposed mesalazine |
| title_fullStr | Radiation-induced morphea of the breast – characterization and treatment of fibroblast dysfunction with repurposed mesalazine |
| title_full_unstemmed | Radiation-induced morphea of the breast – characterization and treatment of fibroblast dysfunction with repurposed mesalazine |
| title_short | Radiation-induced morphea of the breast – characterization and treatment of fibroblast dysfunction with repurposed mesalazine |
| title_sort | radiation induced morphea of the breast characterization and treatment of fibroblast dysfunction with repurposed mesalazine |
| topic | Fibrosis Morphea Drug repurposing Breast cancer Mesalazine |
| url | https://doi.org/10.1038/s41598-024-74206-w |
| work_keys_str_mv | AT stephanrkunzel radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT erikklapproth radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT nickzimmermann radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT susannekammerer radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT marioschubert radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT karolinakunzel radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT maximilianhoffmann radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT stephandrukewitz radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT annevehlow radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT jirieitler radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT mariekearriens radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT jessicathiel radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT romykronsteinwiedemann radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT maximilianetietze radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT stefanbeissert radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT bertoldrenner radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT alielarmouche radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine AT claudiagunther radiationinducedmorpheaofthebreastcharacterizationandtreatmentoffibroblastdysfunctionwithrepurposedmesalazine |