Pharmacological targeting of the protein synthesis mTOR /4E‐ BP 1 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.

Tumor microenvironment and cancer therapy resistance

“…Besides, miR-27a/b-transfected normal fibroblasts show increased expression of TGF-β and α-smooth muscle actin (α-SMA, a marker of CAF), changes that correlate with reduced chemosensitivity of esophageal cancer cells to cisplatin [9]. Despite the tumor-suppressive capacity in certain malignancies including pancreatic ductal adenocarcinoma (PDA) [10,11], CAFs exhibit aggressive proliferation, augmented extracellular matrix (ECM) deposition, enhanced cytokine synthesis/secretion (for instance, FGF7; hepatocyte growth factor (HGF); interleukin 6 (IL-6); PDGF; stromal cell-derived factor 1 (SDF-1); vascular endothelial growth factor (VEGF)) [5], a unique stromal phenotype characterized with a chemoresistance-triggering secretome that can be abolished upon mTOR/4E-BP1 translation pathway blockade [12].…”

Cancer-associated fibroblasts as target and tool in cancer therapeutics and diagnostics

“…The mTOR/4E-BP1 pathway has been identified as critical player in the production and secretion of CAF-derived factors building up the chemoprotective stroma. Inhibition by SOM230 (somatostatin receptor inhibitor) prevents the activation of the mTOR/4E-BP-1 pathway and sensitizes pancreatic cancer to gemcitabine in vivo [28]. Oncologists are not only interested in the tumour-environment as a possible target but also to include the stromal reaction in the outcome measurements of clinical trials [38].…”

Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness

“…Among the fibroblasts, cancer-associated fibroblasts (CAFs), also named activated pancreatic stellate cells, have been largely reported as impacting PDA development (9). Moreover, CAFs are predominantly responsible for the secretion of various molecules that lead to highly fibrous tumors (10) and enhance tumor growth (11,12). Because of this fibrotic density, PDAs are characterized by numerous areas of low vascular density (13) and hypoxic regions, where tumor cells…”