Stroma-derived extracellular vesicles deliver tumor-suppressive miRNAs to pancreatic cancer cells

// Song Han 1 , David H. Gonzalo 2, * , Michael Feely 2, * , Carlos Rinaldi 3 , Sayali Belsare 3 , Haiyan Zhai 4 , Krishan Kalra 4 , Michael H. Gerber 1 , Christopher E. Forsmark 5 and Steven J. Hughes 1 1 Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA 2 Department of Pathology, University of Florida College of Medicine, Gainesville, FL, USA 3 Department of Biomedical Engineering, University of Florida College of Medicine, Gainesville, FL, USA 4 BioGenex Laboratories, Fremont, CA, USA 5 Division of Gastroenterology, University of Florida College of Medicine, Gainesville, FL, USA * These authors contributed equally to this work Correspondence to: Song Han, email: song.han@surgery.ufl.edu Keywords: pancreatic cancer; microenvironment; exosomes; microvesicles; miR-145 Received: October 03, 2017      Accepted: November 28, 2017      Published: December 20, 2017 ABSTRACT The biology of tumor-associated stroma (TAS) in pancreatic ductal adenocarcinoma (PDAC) is not well understood. The paradoxical observation that stroma-depletion strategies lead to progression of PDAC reinforced the need to critically evaluate the functional contribution of TAS in the initiation and progression of PDAC. PDAC and TAS cells are unique in their expression of specific miRNAs, and this specific miRNA expression pattern alters host to tumor microenvironment interactions. Using primary human pancreatic TAS cells and primary xenograft PDAC cells co-culture, we provide evidence of miRNA trafficking and exchanging between TAS and PDAC cells, in a two-way, cell-contact independent fashion, via extracellular vesicles (EVs) transportation. Selective packaging of miRNAs into EVs led to enrichment of stromal specific miR-145 in EVs secreted by TAS cells. Exosomes, but not microvesicles, derived from human TAS cells demonstrated a tumor suppressive role by inducing PDAC cell apoptosis. This effect was mitigated by anti-miR-145 sequences. Our data suggest that TAS-derived miRNAs are delivered to adjacent PDAC cells via exosomes and suppress tumor cell growth. These data highlight that TAS cells secrete exosomes carrying tumor suppressive genetic materials, a possible anti-tumor capacity. Future work of the development of patient-derived exosomes could have therapeutic implications for unresectable PDAC.