Glioblastoma-derived glutamate drives… (F31NS151623) – Project Grant to University Of Miami

Abstract: Tumor-associated astrocytes (taas) are a key component of the glioblastoma (GBM) tumor microenvironment (TME) and exhibit a reactive phenotype marked by increased proliferation and complement component 3 (C3) and glial fibrillary acidic protein (gfap) expression. Taas provide cancer cells with metabolic support, enhance TME immunosuppression, and promote treatment resistance. However, the mechanisms that drive TAA reprogramming remain poorly understood. Previous studies showed that GBM cells secrete supraphysiological levels of glutamate into the TME via the cystine-glutamate antiporter, SLC7A11. Furthermore, glutamate signaling enhances GBM cell invasion and proliferation. However, the potential role of 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 taas as a nexus of aberrant glutamate signaling in GBM. In preliminary experiments, i found that glutamate treatments, at levels found in patient tumors, increases astrocyte proliferation and upregulates gfap and C3, which has emerged as a pro-tumorigenic signal that increases GBM cell stemness and immunosuppressive programming in myeloid cells. Mouse and patient-derived GBM cell models secrete varying levels of glutamate depending on SLC7A11 expression. Conditioned media (CM) from GBM cell lines that secrete high levels of glutamate more robustly induce C3 and gfap expression and proliferation than those with lower glutamate secretion. This effect is mitigated by pharmacological or genetic SLC7A11 inhibition. Moreover, CO-implantation of GBM cells with astrocytes accelerated tumorigenesis, while C3 knockout mice exhibited extended GBM survival compared to wild-type controls. CM from astrocytes stimulated with glutamate or supernatants from high- but not low- glutamate -secreting GBM cell lines potentiated GBM cell proliferation. Finally, SLC7A11 expression correlates with C3 and gfap expression in GBM patients. Thus, my central hypothesis is that SLC7A11-mediated glutamate secretion reprograms taas, which promote GBM via upregulation of C3. Aim 1 will test the hypothesis that glutamatergic activation of astrocytes promotes GBM via secretion of C3. I will evaluate whether glutamatergic activation of astrocytes promotes tumorigenesis via CO-implantation of WT versus C3 KO astrocytes with cancer cells. I will also interrogate the role of astrocyte-derived C3 in promoting cancer cell proliferation and stemness. Aim 2 will test the hypothesis that GBM cells drive reactive TAA programming via SLC7A11-dependent glutamate secretion. I will genetically modulate SLC7A11 in GBM cells to determine the role of cancer cell-derived glutamate on reactive astrocyte cytokine expression, morphology, proliferation, and expression profile. I will also evaluate the impact of SLC7A11 inhibition on survival and TME reprogramming. Collectively, these studies will define the role of SLC7A11-dependent glutamate signaling in TAA reprogramming and identify C3, and SLC7A11 as potential therapeutic targets to disrupt GBM-TME interactions.

Glioblastoma-derived glutamate drives pro-tumorigenic reactive astrocytes

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