Context-Dependent PrPᶜ Signaling in Cancer Stemness, Mesenchymal Stromal Cell Repair, and Extracellular Vesicle...

Cellular prion protein (PrPᶜ), encoded by PRNP, is increasingly recognized as a context-dependent regulator of cellular stress adaptation and intercellular communication beyond its canonical role as the physiological precursor of disease-associated prion conformers. Through its localization in membrane microdomains and interactions with receptors, adhesion molecules, chaperones, and extracellular vesicles (EVs), PrPᶜ has been linked to redox and mitochondrial homeostasis, survival signaling, senescence regulation, and tissue repair. However, these functions are neither uniformly pathogenic nor protective. In malignant systems, PrPᶜ-associated pathways may be co-opted to support cancer stem-like properties, mesenchymal plasticity, migration, therapeutic resistance, and EV-mediated tumor communication. In this review, we focused on regenerative systems, specifically in mesenchymal stem/stromal cells (MSCs). The most consistent perturbation-based evidence linked PrPᶜ to hypoxic and oxidative stress resistance, mitochondrial integrity, senescence control, paracrine competence, and reparative activity. Broader functions of PrPᶜ in other stem and progenitor populations were outside the primary scope. We further evaluated EV-associated PrPᶜ by distinguishing analytical association, regulated vesicular sorting and directly demonstrated recipient-cell signaling. Direct cross-system comparison indicates that causal support is strongest in selected colorectal-cancer and direct EV-signaling models, whereas regenerative MSC and MSC-EV evidence remains more model-specific and typically derives from multicomponent priming or rescue paradigms. We propose an evidence-informed, context-dependent framework in which PrPᶜ modulation is guided by cellular identity, disease context, and experimentally demonstrated functional dependence rather than by PRNP expression or PrPᶜ abundance alone.