1. <scp>FAK</scp> activity in cancer‐associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer
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Rémi Samain, Vinothini Rajeeve, Stéphane Pyronnet, Ismahane Belhabib, Manon Strehaiano, Stéphanie Cassant-Sourdy, Muriel Mathonnet, Yvan Martineau, Aurélie Perraud, Emilie Decaup, Cindy Neuzillet, Amandine Alard, Richard Tomasini, Corinne Bousquet, David D. Schlaepfer, Alexia Brunel, Christine Jean, Oliver M. T. Pearce, Jérôme Cros, Sonia Zaghdoudi, Julia Rochotte, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, University of California [San Diego] (UC San Diego), University of California, Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Curie [Paris], Queen Mary University of London (QMUL), Université de Limoges (UNILIM), Barts Cancer Institute [London, UK], Cancer Research UK, CRUK: A27947 Fondation pour la Recherche Médicale, FRM: FRM ING20150532688, 40493 Ligue Contre le Cancer: RAB17029BBA, RMA04002BPA, RAB20008BBA PLBIO2015‐115, PAIR 2018‐080, IP/SC16060 G16001BB, We thank Dr Frédéric Lagarrigue (IPBS, Toulouse) for his help with beta‐1 integrin assay, and Marcin Domagala and Sophie Gazzola (CRCT, Toulouse) for their advice on macrophage experiments. We thank Laetitia Ligat (CRCT), Sophie Allart (CPTP) and Astrid Canivet‐Laffitte (CPTP) for their help and expertise in microscopy, Manon Farce (CRCT) for her help and flow cytometry expertise, and Loic Van Den Berghe and Christelle Segura for their help in lentivirus production and expertise in vectorology. The authors also acknowledge Dr Francois‐Xavier Frenois from the Imag'IN platform (IUC, Toulouse, France) for his help and expertise on Definiens Tissue Studio® and Dr Pedro Cutillas from the Centre for Haemato‐Oncology (Barts Cancer Institute, Queen Mary University of London, UK). We would like to thank Servier Medical Art ( https://smart.servier.com ) for graphics used in the figures. This work was supported by LNCC (Ligue Nationale Contre le Cancer RAB20007BBA, RAB20008BBA and RAB17029BBA), the Canceropole Grand Sud‐Ouest (RMA04002BPA), the Labex TOUCAN, the Toulouse University IDEX (G16001BB), the PHUC CAPTOR, la Fondation Bristol‐Myers Squibb and the French National Institute of Cancer (INCa, PLBIO2015‐115, PAIR 2018‐080). I.B is a recipient of LNCC fellowship (IP/SC16060). E.D. and J.R. salaries are funded, respectively, by Fondation pour la Recherche Médicale (FRM ING20150532688) and the French National Institute of Cancer (PLBIO2015‐115), and R.S. was a recipient of a fellowship from FRM (#40493). C.J. was recipient of a fellowship from the LNCC. O.M.T.P is a recipient of a Cancer Research UK and Credit Suisse fellowship (A27947).
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0301 basic medicine ,Medicine (General) ,Stromal cell ,[SDV]Life Sciences [q-bio] ,pancreatic ductal adenocarcinoma ,QH426-470 ,Biology ,Article ,extracellular matrix remodelling ,Fibroblast migration ,Metastasis ,Focal adhesion ,Extracellular matrix ,03 medical and health sciences ,chemistry.chemical_compound ,R5-920 ,0302 clinical medicine ,Cell Line, Tumor ,Pancreatic cancer ,Genetics ,medicine ,Humans ,metastasis ,Phosphorylation ,Cancer ,Biomarkers & Diagnostic Imaging ,cancer‐associated fibroblasts ,focal adhesion kinase ,Tyrosine phosphorylation ,Articles ,Fibroblasts ,Prognosis ,medicine.disease ,3. Good health ,Pancreatic Neoplasms ,030104 developmental biology ,chemistry ,Cancer research ,Molecular Medicine ,Cancer-Associated Fibroblasts ,cancer-associated fibroblasts ,030217 neurology & neurosurgery ,Carcinoma, Pancreatic Ductal - 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., 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).
- Published
- 2020
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