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

• Published in: EMBO molecular medicine 2020-11, Vol.12 (11), p.e12010-n/a
• Main Authors: Zaghdoudi, Sonia, Decaup, Emilie, Belhabib, Ismahane, Samain, Rémi, Cassant‐Sourdy, Stéphanie, Rochotte, Julia, Brunel, Alexia, Schlaepfer, David, Cros, Jérome, Neuzillet, Cindy, Strehaiano, Manon, Alard, Amandine, Tomasini, Richard, Rajeeve, Vinothini, Perraud, Aurélie, Mathonnet, Muriel, Pearce, Oliver MT, Martineau, Yvan, Pyronnet, Stéphane, Bousquet, Corinne, Jean, Christine
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal - drug therapy; Cell Line, Tumor; Cell number; Chemoresistance; Development and progression; EMBO02; EMBO03; Extracellular matrix; extracellular matrix remodelling; Fibroblasts; Fibrosis; Focal adhesion kinase; Gene expression; Humans; Kinases; Leukocyte migration; Life Sciences; Macrophages; Medical prognosis; Metastases; Metastasis; Pancreatic cancer; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms; Patients; Phosphorylation; Prognosis; Proteins; Stromal cells; Tumors; Tyrosine
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202012010

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. Synopsis Understanding how cancer‐associated fibroblasts (CAFs) promote PDAC progression is of major interest given the poor prognosis of patients. This study identifies a druggable key regulator of CAF‐induced tumour cell metastasis and a prognostic factor: the protein Focal Adhesion Kinase (FAK). FAK activity within CAFs was an independent prognostic marker for Disease Free Survival (DFS) and Overall Survival (OS) in a cohort of 120 PDAC patients. Activation of FAK within CAFs did not necessarily impact tumour growth, but favored tumour spread in vivo . Fibroblastic FAK activity promoted extracellular matrix (ECM) track formation used by tumor cells to invade, and MCP‐1 secretion leading to M2 macrophage recruitment to primary tumor site. Specific FAK inactivation within CAFs “normalized” the tumor stroma (decreased fibrosis and pro‐tumor immunity) and drastically decreased spontaneous metastasis. PDAC patients may benefit from treatment with FAK kinase inhibitor (already clinically available) through the inhibition of the deleterious pro‐metastatic action of CAFs. Graphical Abstract Understanding how cancer‐associated fibroblasts (CAFs) promote PDAC progression is of major interest given the poor prognosis of patients. This study identifies a druggable key regulator of CAF‐induced tumour cell met