Anti-metastatic potential of somatostatin analog SOM230: Indirect pharmacological targeting of pancreatic cancer-associated fibroblasts

// Siham Moatassim-Billah 1, 2, * , Camille Duluc 1, * , Remi Samain 1, * , Christine Jean 1 , Aurelie Perraud 3 , Emilie Decaup 1 , Stephanie Cassant-Sourdy 1 , Youssef Bakri 2 , Janick Selves 4 , Herbert Schmid 5 , Yvan Martineau 1 , Muriel Mathonnet 3 , Stephane Pyronnet 1 , Corinne Bousquet 1 1 Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France 2 Biochemistry-Immunology Laboratory, Faculty of Sciences Rabat, University Mohammed V - Agdal, Rabat, Morocco 3 EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France 4 Pathology Department, Institut Universitaire du Cancer de Toulouse, Toulouse, France 5 Oncology Global Development, Novartis Pharmaceuticals, Basel, Switzerland * These authors have contributed equally to this work Correspondence to: Corinne Bousquet, email: corinne.bousquet@inserm.fr Keywords: pancreatic cancer, tumor microenvironment, cancer-associated fibroblasts, metastasis, somatostatin analog SOM230 Received: July 16, 2015      Accepted: March 31, 2016      Published: May 12, 2016 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.