Open AccessFAK activity in cancer‐associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer
Author(s) -
Zaghdoudi Sonia,
Decaup Emilie,
Belhabib Ismahane,
Samain Rémi,
CassantSourdy Stéphanie,
Rochotte Julia,
Brunel Alexia,
Schlaepfer David,
Cros Jérome,
Neuzillet Cindy,
Strehaiano Ma,
Alard Amandine,
Tomasini Richard,
Rajeeve Vinothini,
Perraud Aurélie,
Mathonnet Muriel,
Pearce Oliver MT,
Martineau Yvan,
Pyronnet Stéphane,
Bousquet Corinne,
Jean Christine
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012010
Subject(s) - focal adhesion , pancreatic cancer , cancer research , stromal cell , extracellular matrix , cancer associated fibroblasts , tyrosine kinase , cancer , pathology , medicine , biology , cancer cell , phosphorylation , signal transduction , microbiology and biotechnology
Cancer‐associated fibroblasts ( CAF s) 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 CAF s has not yet been identified. Here we report that focal adhesion kinase ( FAK ) activity (evaluated based on 397 tyrosine phosphorylation level) in CAF s 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 CAF s, modifies ECM track generation and negatively impacts M2 macrophage polarization and migration. Thus, FAK activity within CAF s appears as an independent PDAC prognostic marker and a druggable driver of tumour cell invasion.