title: Anti-metastatic potential of somatostatin analog SOM230: Indirect pharmacological targeting of pancreatic cancer-associated fibroblasts.
abstract: Pancreatic ductal adenocarcinoma (PDA) shows a rich stroma where cancer-associated fibroblasts (CAFs) represent the major cell type. CAFs are master secretors of proteins with pro-tumor features. CAF targeting remains a promising challenge for PDA, a devastating disease where treatments focusing on cancer cells have failed. We previously introduced a novel pharmacological CAF-targeting approach using the somatostatin analog SOM230 (pasireotide) that inhibits protein synthesis in CAFs, and subsequent chemoprotective features of CAF secretome. Using primary cultures of CAF isolated from human PDA resections, we here report that CAF secretome stimulates in vitro cancer cell survival, migration and invasive features, that are abolished when CAFs are treated with SOM230. Mechanistically, SOM230 inhibitory effect on CAFs depends on the somatostatin receptor subtype sst1 expressed in CAFs but not in non-activated pancreatic fibroblasts, and on protein synthesis shutdown through eiF4E-Binding Protein-1 (4E-BP1) expression decrease. We identify interleukin-6 as a SOM230-inhibited CAF-secreted effector, which stimulates cancer cell features through phosphoinositide 3-kinase activation. In vivo, mice orthotopically co-xenografted with the human pancreatic cancer MiaPaCa-2 cells and CAFs develop pancreatic tumors, on which SOM230 treatment does not inhibit growth but abrogates metastasis. Consistently, CAF secretome stimulates epithelial-to-mesenchymal transition in cancer cells, which is reversed upon CAF treatment with SOM230. Our results highlight a novel promising anti-metastatic potential for SOM230 indirectly targeting pancreatic cancer cell invasion through pharmacological inhibition of stromal CAFs.
authors.affiliation: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.|Biochemistry-Immunology Laboratory, Faculty of Sciences Rabat, University Mohammed V-Agdal, Rabat, Morocco.
authors.forename: Siham
authors.initials: S
authors.lastname: Moatassim-Billah
authors.affiliation: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Duluc
authors.affiliation: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Samain
authors.affiliation: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Jean
authors.affiliation: EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Perraud
authors.affiliation: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Decaup
authors.affiliation: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Cassant-Sourdy
authors.affiliation: Biochemistry-Immunology Laboratory, Faculty of Sciences Rabat, University Mohammed V-Agdal, Rabat, Morocco.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Bakri
authors.affiliation: Pathology Department, Institut Universitaire du Cancer de Toulouse, Toulouse, France.
authors.forename: Janick
authors.initials: J
authors.lastname: Selves
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals, Basel, Switzerland.
authors.forename: Herbert
authors.initials: H
authors.lastname: Schmid
authors.affiliation: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Martineau
authors.affiliation: EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Mathonnet
authors.affiliation: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pyronnet
authors.affiliation: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Bousquet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D013004:Somatostatin; C517782:pasireotide
keywords: cancer-associated fibroblasts; metastasis; pancreatic cancer; somatostatin analog SOM230; tumor microenvironment