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

Yoav Binenbaum, Eran Fridman, Zvi Yaari, Neta Milman, Avi Schroeder, Gil Ben David, Tomer Shlomi, Ziv Gil*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

257 Scopus citations

Abstract

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 approximately 90 nm 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 triphospho-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, whereas 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. Significance: Harnessing macrophage-derived exosomes as conveyers of antagomiRs augments the effect of chemotherapy against cancer, opening new therapeutic options against malignancies where resistance to nucleotide analogs remains an obstacle to overcome.

Original languageAmerican English
Pages (from-to)5287-5299
Number of pages13
JournalCancer Research
Volume78
Issue number18
DOIs
StatePublished - 15 Sep 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 American Association for Cancer Research.

Fingerprint

Dive into the research topics of 'Transfer of miRNA in macrophage-derived exosomes induces drug resistance in pancreatic adenocarcinoma'. Together they form a unique fingerprint.

Cite this