Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 4; pp. 940 - 951
• Main Authors: Mittapalli, Venugopal R, Madl, Josef, Löffek, Stefanie, Kiritsi, Dimitra, Kern, Johannes S, Römer, Winfried, Nyström, Alexander, Bruckner-Tuderman, Leena
• Format: Journal Article
• Language: English
• Published: United States 15-02-2016
• Subjects: Animals; Cell Differentiation; Dermis - pathology; Disease Progression; Epidermolysis Bullosa Dystrophica - genetics; Epidermolysis Bullosa Dystrophica - pathology; Humans; Mice; Mice, Transgenic; Skin Neoplasms - pathology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-15-1348

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.