title: Mechanotransduction pathways promoting tumor progression are activated in invasive human squamous cell carcinoma.
abstract: Cutaneous squamous cell carcinomas (SCCs) are commonly diagnosed skin cancers that may progress to invasiveness in the absence of early intervention. Using a murine model of SCC, we have previously demonstrated that activation of the Rho-associated kinase (ROCK) signaling pathway promotes rapid progression of pre-neoplastic lesions to invasive SCC. Herein we demonstrate that in human cutaneous SCC, ROCK signaling is increasingly up-regulated with tumor progression in both tumor cells and cells of the tumor microenvironment and is accompanied by key tumor-promoting changes in the extracellular matrix protein composition. The mechanotransduction pathway mediated by integrin signaling through FAK, GSK3β, and the transcription coactivator β-catenin is also progressively activated in human cutaneous SCC. Our observations indicate that ROCK activation is a tumor promoter in human cutaneous SCC and acts via mechanotransduction of signals to β-catenin. Our experiments raise the possibility that inhibition of ROCK signaling could be a useful therapeutic approach to halt cutaneous SCC progression by reducing the signal flux through this pathway to physiologic levels, thereby normalizing the extracellular matrix composition.
authors.affiliation: Division of Surgical Pathology, SA Pathology, Adelaide, Australia.
authors.forename: S Jan
authors.initials: SJ
authors.lastname: Ibbetson
authors.forename: Natasha T
authors.initials: NT
authors.lastname: Pyne
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Pollard
authors.forename: Michael F
authors.initials: MF
authors.lastname: Olson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Samuel
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D016023:Integrins / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D009361:Neoplasm Invasiveness; D012878:Skin Neoplasms / Q000201:enzymology / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D005353:Fibronectins; D016023:Integrins; C082838:Postn protein, mouse; D051176:beta Catenin; D003094:Collagen; D051416:Focal Adhesion Protein-Tyrosine Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D054460:rho-Associated Kinases; D038362:Glycogen Synthase Kinase 3