title: Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is extremely stroma-rich. Cancer-associated fibroblasts (CAFs) secrete proteins that activate survival and promote chemoresistance of cancer cells. Our results demonstrate that CAF secretome-triggered chemoresistance is abolished upon inhibition of the protein synthesis mTOR/4E-BP1 regulatory pathway which we found highly activated in primary cultures of α-SMA-positive CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor. The SOM230 analogue (Pasireotide) activates the sst1 receptor and inhibits the mTOR/4E-BP1 pathway and the resultant synthesis of secreted proteins including IL-6. Consequently, tumour growth and chemoresistance in nude mice xenografted with pancreatic cancer cells and CAFs, or with pieces of resected human PDACs, are reduced when chemotherapy (gemcitabine) is combined with SOM230 treatment. While gemcitabine alone has marginal effects, SOM230 is permissive to gemcitabine-induced cancer cell apoptosis and acts as an antifibrotic agent. We propose that selective inhibition of CAF protein synthesis with sst1-directed pharmacological compounds represents an anti-stromal-targeted therapy with promising chemosensitization potential.
authors.affiliation: INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Duluc
authors.affiliation: INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France Biochemistry-Immunology Laboratory, Faculty of Sciences Rabat, University Mohammed V - Agdal, Agdal, Morocco.
authors.forename: Siham
authors.initials: S
authors.lastname: Moatassim-Billah
authors.affiliation: INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France.
authors.forename: Mounira
authors.initials: M
authors.lastname: Chalabi-Dchar
authors.affiliation: EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Perraud
authors.affiliation: INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Samain
authors.affiliation: Pathology Department, Hôpitaux de Toulouse, Toulouse, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Breibach
authors.affiliation: INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gayral
authors.affiliation: INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cordelier
authors.affiliation: Pathology Department, Hôpitaux de Toulouse, Toulouse, France.
authors.forename: Marie-Bernadette
authors.initials: MB
authors.lastname: Delisle
authors.affiliation: CNRS UMR-5089, Institut de Pharmacologie et de Biologie structurale (IPBS), Université de Toulouse, Toulouse, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Bousquet-Dubouch
authors.affiliation: CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM105; CNRS, UMR7258, Marseille, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Tomasini
authors.affiliation: Novartis Pharmaceuticals, Bales, Switzerland.
authors.forename: Herbert
authors.initials: H
authors.lastname: Schmid
authors.affiliation: EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Mathonnet
authors.affiliation: INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pyronnet
authors.affiliation: INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Martineau
authors.affiliation: INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France corinne.bousquet@inserm.fr.
authors.forename: Corinne
authors.initials: C
authors.lastname: Bousquet
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004195:Disease Models, Animal; D004351:Drug Resistance; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D003841:Deoxycytidine; D013004:Somatostatin; C517782:pasireotide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000093542:Gemcitabine
keywords: cancer‐associated fibroblasts; chemoresistance; pancreatic cancer; pharmacotherapy; protein synthesis and secretion
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