The Impact of Prion Protein on Gliomagenesis: Unraveling Molecular Pathways in Patient-Derived Tumor Stem Cells

Abstract

Glioblastoma (GBM) is an extremely aggressive, recurrent, and incurable tumor characterized by significant cellular and molecular heterogeneity, posing a challenge for advancements in its therapy and scientific research modeling. GBM is sustained by a subpopulation of glioblastoma stem cells (GSCs) responsible for promoting angiogenesis, invasion, and therapy resistance. Preclinical models are crucial in the development of anti-tumor strategies, including in GBM, as they bridge the gap between basic research and clinical translation. Our group previously proposed cellular prion protein (PrPC) as a scaffold protein that integrates signaling platforms involved in GSC maintenance. It has been shown that PrPC silencing inhibits tumor growth, induces cell death, reduces the expression of self-renewal markers and cell adhesion-associated proteins, and dysregulates important pathways in tumor biology. Since prior data from our group suggest PrPC as a GSC marker, a deeper understanding of which molecules and intracellular pathways are modulated by this protein in preclinical models, such as patient-derived xenograft (PDX) cells, patient-derived glioblastoma stem cells (GSCs or tumoroids), and co-culture of GSCs with brain organoids (GLICO), is essential for identifying molecular targets that contribute to GBM treatment.