Oncotarget

Research Papers:

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

Siham Moatassim-Billah, Camille Duluc, Rémi Samain, Christine Jean, Aurélie Perraud, Emilie Decaup, Stéphanie Cassant-Sourdy, Youssef Bakri, Janick Selves, Herbert Schmid, Yvan Martineau, Muriel Mathonnet, Stéphane Pyronnet and Corinne Bousquet _

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Oncotarget. 2016; 7:41584-41598. https://doi.org/10.18632/oncotarget.9296

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Abstract

Siham Moatassim-Billah1,2,*, Camille Duluc1,*, Rémi Samain1,*, Christine Jean1, Aurélie Perraud3, Emilie Decaup1, Stéphanie Cassant-Sourdy1, Youssef Bakri2, Janick Selves4, Herbert Schmid5, Yvan Martineau1, Muriel Mathonnet3, Stéphane Pyronnet1, Corinne Bousquet1

1Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France

2Biochemistry-Immunology Laboratory, Faculty of Sciences Rabat, University Mohammed V - Agdal, Rabat, Morocco

3EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France

4Pathology Department, Institut Universitaire du Cancer de Toulouse, Toulouse, France

5Oncology 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.


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