CNSC-05. GLIOBLASTOMA-DERIVED GLUTAMATE DRIVES TUMOR-ASSOCIATED ASTROCYTE REACTIVITY

Abstract Tumor-associated astrocytes (TAAs) are a key component of the glioblastoma (GBM) tumor microenvironment (TME) and exhibit a reactive phenotype that provides cancer cells with metabolic support, enhances TME immunosuppression, and that increases treatment resistance. However, the mechanisms that drive TAA reprogramming remain poorly understood. Previous studies showed that GBM cells secrete supraphysiologic levels of glutamate into the TME via the cystine-glutamate antiporter, SLC7A11, and that autocrine glutamate signaling enhances GBM cell invasion and proliferation. Nevertheless, the potential role glutamate in reshaping the TME remains unexplored. Astrocytes are critical regulators of glutamatergic homeostasis in the brain. They express a range of glutamate transporters, receptors, and metabolic enzymes positioning themselves as a nexus of aberrant glutamate signaling in GBM. We found that glutamate increases both astrocyte proliferation and the expression of reactive astrocyte markers, including complement component 3 (C3). Additionally, mouse and patient-derived GBM cell models secrete varying levels of glutamate dependent on their SLC7A11 expression. In GBM patients, SLC7A11 expression correlates with reactive astrocyte marker expression. When co-cultured with astrocytes, GBM cell lines that secrete high levels of glutamate more robustly induce reactive astrocyte marker expression and proliferation than those with lower glutamate secretion. Furthermore, pharmacological inhibition of SLC7A11 mitigates reactive astrocyte induction by high- but not low-glutamate-secreting cancer cells. Finally, co-implantation of GBM cells with astrocytes accelerated tumorigenesis, while C3 knockout mice have elongated GBM survival compared to wild-type controls. Collectively, this study defines a novel role for SLC7A11-dependent glutamate signaling in TAA reprogramming and identify therapeutic targets that disrupt GBM–TME interactions to improve patient outcomes. Future studies will investigate how aberrant glutamate signaling endows astrocytes with pro-tumorigenic properties, such as promoting GBM cell proliferation, migration, stemness, and resistance to therapy.