CAN-15-1348R-Supplementary Figure-S3 from Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression
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posted on 2023-03-30, 23:48 authored by Venugopal R. Mittapalli, Josef Madl, Stefanie Löffek, Dimitra Kiritsi, Johannes S. Kern, Winfried Römer, Alexander Nyström, Leena Bruckner-TudermanImages of Western blot analysis
Funding
German Research Foundation, DFG
Debra International and the German Federal Ministry for Education and Research, BMBF, under the frame of Erare-2, the ERA-Net for Research on Rare Diseases
Ministry of Science, Research and the Arts of Baden-Württemberg
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ARTICLE ABSTRACT
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.Usage metrics
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