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.

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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