title: Injury-Driven Stiffening of the Dermis Expedites Skin Carcinoma Progression.
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.
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Venugopal R
authors.initials: VR
authors.lastname: Mittapalli
authors.affiliation: Institute of Biology II, Albert Ludwigs University of Freiburg, Freiburg, Germany. BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Madl
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Löffek
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Kiritsi
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Johannes S
authors.initials: JS
authors.lastname: Kern
authors.affiliation: Institute of Biology II, Albert Ludwigs University of Freiburg, Freiburg, Germany. BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Römer
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nyström
authors.affiliation: Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany. BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg, Germany. bruckner-tuderman@uniklinik-freiburg.de.
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D020405:Dermis / Q000473:pathology*; D018450:Disease Progression; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D012878:Skin Neoplasms / Q000473:pathology*