FAK activity in cancer‐associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer

• DOI: 10.15252/emmm.202012010
• Publication Date: 2020-10-07T12:12:03Z
• Authors: Sonia Zaghdoudi; Emilie Decaup; Ismahane Belhabib; Rémi Samain; Stéphanie Cassant...; Julia Rochotte; Alexia Brunel; David Schlaepfer; Jérome Cros; Cindy Neuzillet; Manon Strehaiano; Amandine Alard; Richard Tomasini; Vinothini Rajeeve; Aurélie Perraud; Muriel Mathonnet; Oliver MT Pearce; Yvan Martineau; Stéphane Pyronnet; Corinne Bousquet; Christine Jean
• Keywords: 0301 basic medicine; Medicine (General); [SDV]Life Sciences [q-bio]; 610; pancreatic ductal adenocarcinoma; QH426-470; Cell Line; extracellular matrix remodelling; 03 medical and health sciences; R5-920; Cancer-Associated Fibroblasts; Cell Line, Tumor; Genetics; metastasis; Humans; Phosphorylation; Tumor; cancer‐associated fibroblasts; Carcinoma; focal adhesion kinase; Articles; Fibroblasts; Prognosis; 3. Good health; Pancreatic Neoplasms; Pancreatic Ductal; cancer-associated fibroblasts; Carcinoma, Pancreatic Ductal

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.