Cellular Prion Protein Coupling to ADAM‐mediated Release of Small Extracellular Vesicles: Pathological Implications in Prostate Cancer Cells

ABSTRACT

The plasma membrane‐anchored cellular prion protein (PrP ^C ), which is well‐known for its role in prion and prion‐like neurodegenerative diseases, has emerged as a critical player in cancer biology. Elevated PrP ^C expression and consequent dysregulation of physiological PrP ^C signalling pathways have been reported in multiple human tumours and are associated with several cancer cell properties, including enhanced proliferation, migration, invasion, metastasis, and drug resistance. Yet, the mechanisms by which altered PrP ^C signalling contributes to cancer biology remain insufficiently understood, in part because the physiological roles of PrP ^C are still incompletely characterized. Here, we identify PrP ^C as a signalling regulator of the release of small extracellular vesicles (EVs) through its coupling to ADAM10 and ADAM17 sheddases, whose proteolytic activity is essential for EV detachment from the plasma membrane. Such PrP ^C regulatory function involves NADPH oxidase‐derived reactive oxygen species, ERK1/2 MAP kinases, and 3‐phosphoinositide‐dependent kinase (PDK1), which collectively fine‐tune ADAM activity at the plasma membrane. In prostate cancer cells, PrP ^C overexpression disrupts this signalling balance. PrP ^C overcoupling to NADPH oxidase promotes ADAM17 overactivity at the plasma membrane and subsequent excessive release of small EVs. Functionally, these EVs sustain the high proliferative capacity of aggressive PC3 prostate cancer cells. Our findings uncover a previously unrecognized mechanism whereby PrP ^C controls the homeostatic release of small EVs via ADAMs, and whose dysregulation fuels the proliferation of prostate cancer cells. These data highlight the PrP ^C –ADAM17–EV axis as a potential therapeutic target in PrP ^C ‐driven cancers.