Cellular prion protein drives mesenchymal identity and microenvironment interaction in glioblastoma

The cellular prion protein (PrP^C) plays crucial roles in regulating cellular functions essential for maintaining brain homeostasis. Its dysregulation has been linked to cancer progression and increased tumor aggressiveness, particularly in glioblastoma (GBM). GBM is the most lethal subtype of glioma, characterized by high invasiveness, molecular diversity, and poor response to therapy. Notably, the mesenchymal (MES) molecular subtype of GBM is characterized by its resistance to therapy, rapid recurrence, and strong interactions with the tumor microenvironment. This complexity makes GBM treatment especially challenging. Recent research suggests that PrP^C may contribute to GBM maintenance, positioning it as a potential regulator of malignant features. However, the connection between PrP^C and the MES subtype of GBM remains poorly understood. Using GBM-MES avatar model and PRNP CRISPR-mediated gene editing, we demonstrate that PrP^C plays a critical role in sustaining the MES subtype of GBM. Knocking out PrP^C (PrP^C-KO) leads to the loss of MES markers and a shift toward a proneural/neural progenitor-like gene signature. Additionally, PrP^C deletion increases sensitivity to radiation and extends survival in orthotopic xenograft models. Importantly, PrP^C-KO impairs macrophage recruitment and disrupts cell-extracellular matrix (ECM) interactions, resulting in reduced adhesion to vitronectin (VN) and fibronectin (FN), decreased adhesion strength to FN, and diminished invasive capacity. Finally, we show that PrP^C loss reduces protein levels of CD44, ITGB3, and paxillin, highlighting a potential mechanism by which PrP^C modulates ECM-dependent tumor behavior. Our findings identify PrP^C as a key driver of MES features in GBM by promoting tumor-microenvironment interactions and regulating cellular plasticity.