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

Song Han,Carlos Rinaldi,David H Gonzalo,Michael H Gerber,Christopher E Forsmark,Steven J Hughes,Sayali Belsare,Krishan Kalra,Michael Feely,Haiyan Zhai

doi:10.18632/oncotarget.23532

Song Han, Carlos Rinaldi + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.23532

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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.

Highlights

IntroductionThe majority of pancreatic adenocarcinoma (PDAC) is tumor-associated stroma (TAS)
By volume, the majority of pancreatic adenocarcinoma (PDAC) is tumor-associated stroma (TAS)
We aimed to confirm that the exchange of miRNAs between TAS cells and pancreatic ductal adenocarcinoma (PDAC) cells is mediated by extracellular vesicles (EV), and to further understand how such an exchange might impact the biology of PDAC

Summary

Introduction

The majority of pancreatic adenocarcinoma (PDAC) is tumor-associated stroma (TAS). Multiple groups challenged this paradigm [4,5,6]; they demonstrated that depletion of PDAC stroma or disruption of hedgehog signaling in differing in vivo models resulted in acceleration of tumor progression. These studies provide compelling evidence of the importance, complexity, and plasticity of TAS, that reinforces the need for improving our understanding of interactions between TAS and PDAC cells with translational implications for future therapy [7]

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