Cellular Prion Protein Coupling to ADAM‐mediated Release of Small Extracellular Vesicles: Pathological Implications in Prostate Cancer Cells
4 affiliations
- 1INSERM UMR‐S 1124 Paris France
- 2Université Paris Cité, UMR‐S 1124 Paris France
- 3Ecole Polytechnique, Institut Polytechnique de Paris CNRS UMR 7654 Palaiseau France
- 4Université Paris Cité, INSERM U1334, CNRS UMR8175 Paris France
Abstract
The plasma membrane‐anchored cellular prion protein (PrPC), which is well‐known for its role in prion and prion‐like neurodegenerative diseases, has emerged as a critical player in cancer biology. Elevated PrPC expression and consequent dysregulation of physiological PrPC 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 PrPC signalling contributes to cancer biology remain insufficiently understood, in part because the physiological roles of PrPC are still incompletely characterized. Here, we identify PrPC 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. SuchPrPC 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, PrPC 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 PrPC–ADAM17–EV axis as a potential therapeutic target in PrPC‐driven cancers.
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BibTeX
@article{bizingre2026cellular,
title = {{Cellular Prion Protein Coupling to ADAM‐mediated Release of Small Extracellular Vesicles: Pathological Implications in Prostate Cancer Cells}},
author = {Chloé Bizingre and Flavien Picard and Florence Roussel and Clara Bianchi and Aurélie Alleaume‐Butaux and Maud Chevé and Hector Ardila‐Osorio and Mathéa Pietri and Grégory Lavieu and Anne Baudry and Benoit Schneider},
journal = {Journal of Extracellular Biology},
year = {2026},
month = nov,
doi = {10.1002/jex2.70195},
url = {https://hal.science/hal-05851371v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Cellular Prion Protein Coupling to ADAM‐mediated Release of Small Extracellular Vesicles: Pathological Implications in Prostate Cancer Cells
AU - Chloé Bizingre
AU - Flavien Picard
AU - Florence Roussel
AU - Clara Bianchi
AU - Aurélie Alleaume‐Butaux
AU - Maud Chevé
AU - Hector Ardila‐Osorio
AU - Mathéa Pietri
AU - Grégory Lavieu
AU - Anne Baudry
AU - Benoit Schneider
PY - 2026
DA - 2026/11/01
JO - Journal of Extracellular Biology
DO - 10.1002/jex2.70195
UR - https://hal.science/hal-05851371v1
AB - The plasma membrane‐anchored cellular prion protein (PrPC), which is well‐known for its role in prion and prion‐like neurodegenerative diseases, has emerged as a critical player in cancer biology. Elevated PrPC expression and consequent dysregulation of physiological PrPC 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 PrPC signalling contributes to cancer biology remain insufficiently understood, in part because the physiological roles of PrPC are still incompletely characterized. Here, we identify PrPC 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. SuchPrPC 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, PrPC 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 PrPC–ADAM17–EV axis as a potential therapeutic target in PrPC‐driven cancers.
SN - 2768-2811
ER -