TMOD-05. GLIOMA-ASSOCIATED OLIGODENDROCYTE PROGENITOR CELLS’ DYNAMIC PATTERNS SUGGEST FUNCTIONAL ADAPTATIONS DURING GLIOMA PROGRESSION IN A UNIQUE MOUSE MODEL

Abstract Gliomas account for more than one-third of brain tumors in children, with high fatality rate despite aggressive adjuvant treatment. Two-thirds of survivors suffer from health conditions due to the toxicity of conventional therapies. Notably, gliomas with the BRAFV600E mutation, occurring in ~20% of all glioma cases, are difficult to treat and have a high risk for progression, especially when combined with CDKN2A deletion. The mechanisms for glioma progression remain unclear and unraveling them could lead to therapies that inhibit glioma progression, preventing high-grade gliomas. Objectives: To gain mechanistic insights into glioma progression and exploit therapeutically for preventing progression. We developed two novel mouse models for BRAFV600E mutant progressive gliomas – one at high genetic risk for progression and one at intermediate genetic risk for progression. Expression of genetic alterations were induced by injecting compound transgenic mice with adenovirus-Cre. Our new mouse models therefore more faithfully recapitulated the genetic changes accompanying glioma formation and progression from low- to high-grade than earlier mouse models which used the RCAS system to overexpress the oncogene (PMCID: PMC11112369 ). Glioma formation was followed non-invasively by magnetic resonance imaging. Single cell RNA sequencing and spatial transcriptomics were performed and immunofluorescence was used for validation (PMCID: PMC10619673 ). We present new data showing that animal subject survival is significantly shorter in the high risk model than in the low risk model. Our two models with distinct latency can be used for preclinical studies and studies of the changes associated with progression, including in the glioma microenvironment. Analyses revealed temporal, functional, and spatial changes in glioma-associated oligodendrocyte progenitor cells (GA-OPCs) at distinct stages (initiation, expansion, progression) and grades. Our findings that GA-OPCs closely interact with glioma cells and their morphological transformation as gliomas progress, suggest changing functions, including potential roles in phagocytosis and immunomodulation. Understanding the unclear role of glioma microenvironment OPCs in promoting glioma progression could reveal an Achilles heel for targeted therapies.