iPS-derived brain cancer avatars models to study prion function in glioblastoma proneural-mesenchymal status and transformation

• Grant number: 24/04958-9
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: September 01, 2024
• End date: August 31, 2025
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Marilene Hohmuth Lopes
• Grantee: Maria Clara da Silva Souza
• Supervisor: Frank Furnari
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of California, San Diego (UC San Diego), United States
• Associated to the scholarship: 23/12507-4 - The Impact of Prion Protein on Gliomagenesis: Unraveling Molecular Pathways in Patient-Derived Tumor Stem Cells, BP.DD

Abstract

Glioblastoma (GBM), sustained by a subpopulation of stem cells (GSCs), continues to confer an unfavorable prognosis, with a median overall survival of 12-18 months, despite implementing a multimodal therapeutic approach. This condition remains a challenge for advancements in therapeutic strategies and research modeling. GBM is a heterogeneous tumor, and the development of high-throughput approaches has facilitated the robust categorization of this malignancy into distinct subgroups. GBM tumors that have undergone mesenchymal transformation are associated with increased aggressiveness and multitherapy resistance, highlighting the importance of investigating the underlying mechanisms and potential therapeutic targets associated with these subtypes. Our group previously proposed cellular prion protein (PrPC) as a scaffold protein that integrates signaling platforms involved in maintaining GSCs. Our findings demonstrate that the knockout of PrPC in GBM cell lines leads to diminished migration and reduced expression of CD44, a marker associated with the mesenchymal subtype of GBM. Mesenchymal subtypes were characterized by potent invasive abilities and more aggressive behavior. Furthermore, in silico bulk and single-cell transcriptomics, analysis revealed a positive correlation between mesenchymal signatures and PRNP levels in patient-derived GBMs. This observation implies a potential role for PrPC in migratory and invasive properties of GSCs, thereby shedding light on its possible involvement in the mesenchymal transition observed in GBM. Therefore, our study aims to elucidate the interplay between PrPC and GSCs in the context of mesenchymal status and transformation using hiPSC-derived neural progenitor cells with genetic mutations associated with the molecular subtypes, or cancer avatars.