TMOD-17. Investigating <i>Bai3</i> loss in Glioblastoma Formation

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival of 12-15 months post-diagnosis, and TP53 mutations are detected in ~30% of sporadic GBM cases. Recent studies suggest that the dysregulation of adhesion G-protein coupled receptors (aGPCRs) may play a role in GBM development. Brain-specific angiogenesis inhibitor 3 (BAI3), a member of the BAI1-3 subfamily of aGPCRs, is highly expressed in neuronal and glial cells. Although BAI3 can regulate synaptic plasticity, dendritic morphogenesis, and apoptotic cell clearance, its role as a tumor suppressor and in GBM pathogenesis has yet to be defined. Analysis of TCGA datasets revealed that BAI3 mRNA and protein expression are significantly downregulated in GBM compared to normal brain tissue. To explore this observed decrease in expression of BAI3 in GBM, we generated constitutive Bai3-/- mice, but tumor formation did not occur. Since TP53 is highly mutated in GBM and BAI3 is involved in regulatory brain functions, we generated a Bai3-/-Trp53f/dNestin-Cre mouse model, combining Bai3-/- mice with Trp53f/dNestin-Cre mice to induce the simultaneous loss of Bai3 and Trp53 in neural and glial progenitor cells, the putative cells of origin of GBM. Trp53f/dNestin-Cre mice developed tumors at a frequency of 26%, while the combined loss of Bai3 and Trp53 increased the incidence of GBM formation to 71%, p = 0.0009. Transcriptomic profiling of the tumors revealed a significant suppression of core metabolic pathways in the Bai3-/-Trp53f/dNestin-Cre GBM. Brain tumor-derived cell lines from both genotypes exhibited high expression of neural stem and glial markers, with low expression of mature neuronal markers. These findings suggest that BAI3 functions as a tumor suppressor in TP53-deficient GBM, by impacting core metabolic GBM pathways, and with its loss of expression, causes tumor incidence to increase by 45%.