STEM-07. Unraveling the role of glioma-associated oligodendrocyte progenitor cells and oligodendrocytes in glioma progression

Abstract Background BRAF gene alterations play a significant role in driving disease in pediatric low-grade glioma, the most prevalent brain tumor in children. Despite aggressive adjuvant treatment, tumors with BRAFV600E mutation, especially when paired with CDKN2A deletion, exhibit a high risk of progression from low-grade tumors to fatal, high-grade tumors. The cellular and molecular mechanisms underlying this progression remain poorly understood. Objectives To gain mechanistic insights into glioma progression in BRAFV600E-mutated and CDKN2A-deleted brain tumors and identify therapeutic targets to prevent progression towards high-grade glioma. Methods We developed a novel transgenic mouse model to conditionally induce BRAFV600E expression and CDKN2A deletion upon Cre-mediated recombination by injecting mice with adenovirus-Cre, stimulating gliomas with a high risk for progression. Cellular and molecular dynamics within the tumor microenvironment are studied across different stages of glioma progression using various techniques including magnetic resonance imaging, histology, single-cell RNA sequencing, and immunofluorescence for validation. Results Our analyses revealed spatiotemporal, morphological, and functional changes in glioma-associated oligodendrocyte progenitor cells and oligodendrocytes (GA-OPCs/OLs) during tumor initiation, growth, and progression. Transcriptomic profiling of glioma microenvironment at distinct stages of glioma progression (low-grade, intermediate-grade versus high-grade gliomas) demonstrated functional heterogeneity among GA-OPCs/OLs, with grade/stage-dependent changes related to phagocytosis, immunomodulation, metabolism, and neuronal regulation. Key molecular candidates implicated in glioma progression mediated by GA-OPCs/OLs are identified for further ongoing investigation. Conclusions Our findings highlight the previously underappreciated role of GA-OPCs/OLs in driving glioma progression. This work provides a foundation for developing targeted therapies to inhibit tumor progression and improve outcomes for pediatric patients with high-risk gliomas.