Cnsc-23. role of glial ph-dependent metabolic regulation in glioma progression

Abstract Malignant glioma is a devastating brain cancer with barely any improvement in prognosis over decades. One key mechanism for glioma invasiveness is the dynamic metabolic communication between glioma and surrounding cells shaping the tumor microenvironment. While extracellular acidosis is a pathological hallmark of glioma, pH-dependent mechanisms underlying tumor metabolic reprogramming remain poorly defined. Our study focuses on a glial-enriched sodium-bicarbonate cotransporter, Slc4a4, which was previously identified as intracellular and extracellular pH regulator. While Slc4a4-mediated pH regulation is important for physiological brain function and responses after injury, its role in glioma progression is largely undefined. To begin addressing this question, we analyzed The Cancer Genome Atlas (TCGA) database, finding high Slc4a4 expression correlates with prolonged survival in glioma patients. Corroboratively, Slc4a4 gain-of-function (GOF) drastically decreases tumorigenesis and angiogenesis in patient-derived-xenograft and CRISPR-mediated de novo mouse glioma models. These results are further complemented by loss-of-function (LOF) studies using glial-specific Slc4a4 knockout mice, suggesting an inhibitory role of Slc4a4 in glioma growth and associated angiogenesis. A combination of unbiased metabolomic and cancer-targeted proteomic profiling of Slc4a4 GOF/LOF mouse glioma reveals an inverse correlation between Slc4a4 and a key lipid metabolism protein, FABP5 (Fatty Acid Binding Protein 5), which is coupled with dysregulated lipid metabolism. Moreover, analysis of TCGA database shows inverse expression and survival correlation of Slc4a4 and FABP5 in glioma patients. Further functional study shows that overexpression of FABP5 reverses Slc4a4’s inhibitory effects on glioma growth in immunocompetent mouse glioma model, supporting a functional antagonism between Slc4a4 and FABP5. Together, our study indicates that Slc4a4 plays a protective role in glioma progression by regulating metabolic activities, providing critical insights into pH-dependent metabolic reprogramming in glioma.