FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer.
cancer-associated fibroblasts
extracellular matrix remodelling
focal adhesion kinase
metastasis
pancreatic ductal adenocarcinoma
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
06 11 2020
06 11 2020
Historique:
received:
14
01
2020
revised:
04
09
2020
accepted:
08
09
2020
pubmed:
8
10
2020
medline:
19
8
2021
entrez:
7
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33025708
doi: 10.15252/emmm.202012010
pmc: PMC7645544
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12010Subventions
Organisme : Ligue nationale contre le cancer (LNCC)
ID : RAB17029BBA
Organisme : the PHUC
ID : CAPTOR
Organisme : Labex
ID : TOUCAN
Organisme : Credit Suisse fellowship
ID : A27947
Organisme : Canceropole Grand Sud Ouest
ID : RMA04002BPA
Organisme : Ligue nationale contre le cancer (LNCC)
ID : RAB20008BBA
Organisme : Fondation pour la Recherche Médicale (FRM)
ID : ING20150532688
Organisme : NCI NIH HHS
ID : R01 CA247562
Pays : United States
Organisme : French National Institute of Cancer
ID : PLBIO2015-115
Organisme : Fondation Bristol-Myers Squibb
ID : RAK17028BBP
Organisme : NCI NIH HHS
ID : R01 CA254342
Pays : United States
Organisme : the Toulouse University IDEX
ID : G16001BB
Organisme : Cancer Research UK (CRUK)
ID : A27947
Organisme : Fondation pour la Recherche Médicale (FRM)
ID : 40493
Organisme : Ligue nationale contre le cancer (LNCC)
ID : IP/SC16060
Organisme : French National Institute of Cancer
ID : PAIR 2018-080
Organisme : Ligue nationale contre le cancer (LNCC)
ID : RAB20007BBA
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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