Basal cell carcinoma (BCC) is the most frequent human cancer and is becoming an important health problem in an ageing population. Based on their clinical and histological characteristics, thick BCC are typically divided into low-risk nodular and high-risk infiltrative subtypes, although the underlying mechanisms are poorly understood. We have identified molecular mechanisms that explain the aggressiveness of high-risk infiltrative BCC, with a potential direct clinical impact. In this study, we first show that fibroblasts, TGFbeta and fibronectin are found preferentially in infiltrative human BCC. This allowed us to develop in vivo models for the study of infiltrative BCC, which in turn let us confirm the role of TGFbeta in inducing peritumoral fibronectin deposition and tumor infiltration. We then show that fibronectin promotes adhesion and migration of BCC cell lines through integrin alpha5beta1-mediated phosphorylation of focal adhesion kinase (FAK). Fittingly, inhibition of integrin alpha5beta1 and phospho-FAK both prevent fibronectin-induced migration of BCC cells in vitro as well as BCC infiltration in vivo. Altogether our results open important insights into the pathogenesis of aggressive infiltrative BCC, and identify integrin alpha5beta1 or FAK inhibition as promising strategies for the treatment of advanced BCC.
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