Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of only 9%. Acquired drug resistance is a major factor that limits the effectiveness of chemotherapy. Exosomes, secreted membrane vesicles that range in size from 30–100 nm in diameter, released from epithelial cancer cells can promote drug resistance. However fibroblasts, not epithelial cells, make up the majority of the tumor bulk in PDAC. Despite the long-standing recognition of the prominence of the fibroblasts in PDAC, the mechanisms through which fibroblast-derived exosomes may contribute to chemoresistance following exposure to chemotherapy have not been studied. A molecular-level understanding of possible fibroblast-driven mechanisms of chemoresistance is essential for the development of more effective treatment strategies.

Here, we show that CAFs exposed to chemotherapy play an active role in regulating the survival and proliferation of cancer cells through the hypersecretion of chemoresistance-promoting exosomes. We found that CAFs exposed to gemcitabine (GEM), the most widely used adjuvant therapy for PDAC, increase the release of exosomes. We utilized miRNA-SEQ analysis to identify miRs that were significantly increased in the exosomes of GEM-treated CAFs compared to treatment naïve CAFs and WT pancreatic fibroblasts. Five out of the top 10 hits were miRs that target PTEN. We utilized GW4869, a compound that inhibits exosome secretion, to functionally show in vitro and in vivo that blocking exosome release from GEM-treated CAFs reduces chemotherapy resistance in PDAC cells through restoration of PTEN expression. Collectively, these findings elucidate the role of CAF-derived exosomes in regulating PDAC chemoresistance and suggest that therapeutic strategies design to inhibit exosome release may lead to improved patient response.