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

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.

Downregulation of miR-145-5p in cancer cells�and their�derived exosomes may contribute to�the�development of ovarian cancer by targeting CT

“…Although miR-145 serves crucial roles in the development of cancer, the majority of studies have focused on the original cells, and the expression of miR-145 in exosomes and its effect on OC remains largely unknown. However, one previous study revealed that the exposure of pancreatic ductal adenocarcinoma to miR-145-5p-enriched tumor-associated stroma exosomes cells decreased cell viability in a dose-dependent manner ( 32 ). To the best of our knowledge, the present study is the first to demonstrate the significant downregulation of miR-145-5p expression in OC exosomes, indicating that the enhanced secretion of miR-145 via exosomes may be an underlying approach to treating OC ( 33 , 34 ).…”

The Proteome of Pancreatic Cancer‐Derived Exosomes Reveals Signatures Rich in Key Signaling Pathways

“…A total of 28 mL of conditioned medium was used for exosome preparation after 24 h of incubation. Exosomes were isolated from these conditioned culture media using the ultracentrifugation/ultrafiltration protocol were previously established . Briefly, conditioned culture media were centrifuged at 2000 × g for 30 min to clear dead cells and cell debris.…”

Comprehensive landscape of extracellular vesicle-derived RNAs in cancer initiation, progression, metastasis and cancer immunology

“…EV-miR-143 from normal epithelial prostate cells suppresses the proliferation of adjacent prostate cancer cells [143]. EV-miR-145 from tumor-associated stroma cells impairs the viability and induces the apoptosis of adjacent pancreatic ductal adenocarcinoma cells [144]. EV-miRNAs from liver stem cells inhibit the proliferation and promote the apoptosis of hepatocellular carcinoma (HCC) cells in vitro and in vivo [145].…”