Transfer of miRNA in macrophages-derived exosomes induces drug resistance of pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is known for its resistance to gemcitabine, which acts to inhibit cell growth by termination of DNA replication. Tumor-associated macrophages (TAM) were recently shown to contribute to gemcitabine resistance; however, the exact mechanism of this process is still unclear. Using a genetic mouse model of PDAC and electron microscopy analysis, we show that TAM communicate with the tumor microenvironment via secretion of ~90nm vesicles, which are selectively internalized by cancer cells. Transfection of artificial dsDNA (barcode fragment) to murine peritoneal macrophages and injection to mice bearing PDAC tumors revealed a 4-log higher concentration of the barcode fragment in primary tumors and in liver metastasis than in normal tissue. These macrophage-derived-exosomes (MDE) significantly decreased the sensitivity of PDAC cells to gemcitabine, in-vitro and in-vivo. This effect was mediated by the transfer of miR-365 in MDE. miR-365 impaired activation of gemcitabine by upregulation of the tri-phospho-nucleotide pool in cancer cells and the induction of the enzyme cytidine deaminase; the latter inactivates gemcitabine. Adoptive transfer of miR-365 in TAM induced gemcitabine resistance in PDAC-bearing mice, while immune transfer of the miR-365 antagonist recovered the sensitivity to gemcitabine. Mice deficient of Rab27 a/b genes, which lack exosomal secretion, responded significantly better to gemcitabine than did wildtype. These results identify MDE as key regulators of gemcitabine resistance in PDAC, and demonstrate that blocking miR-365 can potentiate gemcitabine response.

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