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Medientyp: E-Artikel Titel: Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression Beteiligte: Mittapalli, Venugopal R.; Madl, Josef; Löffek, Stefanie; Kiritsi, Dimitra; Kern, Johannes S.; Römer, Winfried; Nyström, Alexander; Bruckner-Tuderman, Leena Erschienen: American Association for Cancer Research (AACR), 2016 Erschienen in: Cancer Research Sprache: Englisch DOI: 10.1158/0008-5472.can-15-1348 ISSN: 0008-5472; 1538-7445 Schlagwörter: Cancer Research ; Oncology Entstehung: Anmerkungen: Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin fragility disorder characterized by injury-driven blister formation, progressive soft-tissue fibrosis, and a highly elevated risk of early-onset aggressive cutaneous squamous cell carcinoma (cSCC). However, the mechanisms underlying the unusually rapid progression of RDEB to cSCC are unknown. In this study, we investigated the contribution of injury-induced skin alterations to cSCC development by using a genetic model of RDEB and organotypic skin cultures. Analysis of RDEB patient samples suggested that premalignant changes to the dermal microenvironment drive tumor progression, which led us to subject a collagen VII hypomorphic mouse model of RDEB to chemical carcinogenesis. Carcinogen-treated RDEB mice developed invasive tumors phenocopying human RDEB-cSCC, whereas wild-type mice formed papillomas, indicating that the aggressiveness of RDEB-cSCC is mutation-independent. The inherent structural instability of the RDEB dermis, combined with repeated injury, increased the bioavailability of TGFβ, which promoted extracellular matrix production, cross-linking, thickening of dermal fibrils, and tissue stiffening. The biophysically altered dermis increased myofibroblast activity and integrin β1/pFAK/pAKT mechanosignaling in tumor cells, further demonstrating that cSCC progression is governed by pre-existing injury-driven changes in the RDEB tissue microenvironment. Treatment of three-dimensional organotypic RDEB skin cultures with inhibitors of TGFβ signaling, lysyl oxidase, or integrin β1–mediated mechanosignaling reduced or bypassed tissue stiffness and limited tumor cell invasion. Collectively, these findings provide a new mechanism by which RDEB tissue becomes malignant and offer new druggable therapeutic targets to prevent cSCC onset. Cancer Res; 76(4); 940–51. ©2015 AACR.</jats:p> Zugangsstatus: Freier Zugang