FAK activity in cancer‐associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer
Sonia Zaghdoudi, Emilie Decaup, Ismahane Belhabib, Rémi Samain, Stéphanie Cassant‐Sourdy, Julia Rochotte, Alexia Brunel, David D. Schlaepfer, Jérôme Cros, Cindy Neuzillet, Manon Strehaïano, Amandine Alard, Richard Tomasini, Vinothini Rajeeve, Aurélie Perraud, Muriel Mathonnet, Oliver M.T. Pearce, Yvan Martineau, Stéphane Pyronnet, Corinne Bousquet, Christine Jean
Abstract
Cancer-associated fibroblasts (CAFs) are considered the most abundant type of stromal cells in pancreatic ductal adenocarcinoma (PDAC), playing a critical role in tumour progression and chemoresistance; however, a druggable target on CAFs has not yet been identified. Here we report that focal adhesion kinase (FAK) activity (evaluated based on 397 tyrosine phosphorylation level) in CAFs is highly increased compared to its activity in fibroblasts from healthy pancreas. Fibroblastic FAK activity is an independent prognostic marker for disease-free and overall survival of PDAC patients (cohort of 120 PDAC samples). Genetic inactivation of FAK within fibroblasts (FAK kinase-dead, KD) reduces fibrosis and immunosuppressive cell number within primary tumours and dramatically decreases tumour spread. FAK pharmacologic or genetic inactivation reduces fibroblast migration/invasion, decreases extracellular matrix (ECM) expression and deposition by CAFs, modifies ECM track generation and negatively impacts M2 macrophage polarization and migration. Thus, FAK activity within CAFs appears as an independent PDAC prognostic marker and a druggable driver of tumour cell invasion.