YAP-mediated mechanotransduction promotes fibrotic activity
Abstract
Fibrosis, a phenotype associated with mortality for a multitude of diseases, has no disease-modifying treatment. We examine if Verteporfin (VP), an inhibitor of the YAP-TEAD complex, currently in wide clinical use for macular degeneration, can inhibit pro-fibrotic gene expression in human dermal fibroblasts. Also, an in vivo approach was taken using a Pten-deficient mouse of progressive skin fibrosis for examining effects on melanoma metastasis. We found that treatment with VP reduced basal expression of a variety of profibrotic genes and prevented a myofibroblast-like phenotype in response to TGFβ1. Indeed, genome-wide expression analysis suggested that VP inhibited a cluster of profibrotic genes with and without added TGFβ1. Preliminary analysis of metastasis to the lung of melanoma tumors in Pten-deficient mice showed a trend towards increased metastasis the absence of Pten expression by fibroblasts; i.e., in a fibrotic microenvironment. My findings support targeting YAP as a potential treatment for fibrotic diseases.