Extracellular RNA transfer from non-malignant human cholangiocytes can promote cholangiocarcinoma growth

Extracellular vesicles (EV) within the cellular secretome are emerging as modulators of pathological processes involved in tumor growth through their ability to transfer donor-derived RNA into recipient cells. While the effects of tumor and stromal cell EVs within the tumor microenvironment have been studied, less is known about the contributions of normal, nontransformed cells. We examined the impact of EVs within the cellular secretome from nonmalignant cells on transformed cell growth and behavior in cholangiocarcinoma cells. These effects were enhanced in the presence of the pro-fibrogenic mediator TGF-beta. We identified miR-195 as a TGF-beta responsive miRNA in normal cells that can be transferred via EV to tumor cells and regulate cell growth, invasion, and migration. The effects of miR-195 involve modulation of the epithelial-mesenchymal transition through direct effects on the transcription factor Snail. These studies provide in vitro and in vivo evidence for the impact of normal cellular secretome on transformed cell growth, show the importance of EV RNA transfer, and identify mechanisms of EV-mediated transfer of miRNA as a contributor to tumor development, which may provide new therapeutic opportunities for targeting human cholangiocarcinoma.

Automated summary

Extracellular vesicles within the cellular secretome play a crucial role in tumor growth, with normal cells transferring miR-195 to cholangiocarcinoma cells via EVs to modulate their growth and behavior. The findings highlight the significance of EV-mediated transfer of miRNA as a mechanism in tumor development, providing potential therapeutic opportunities for targeting human cholangiocarcinoma.