Abstract 3368: Metabolite-driven post-translational modifications regulate mitochondrial homeostasis in the glioblastoma microenvironment

Abstract Glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis, demanding new therapeutic strategies. A key challenge in treating GBM is the complex communication between tumor cells and the surrounding tumor microenvironment (TME), which enhances tumor resilience. This study investigated how metabolites, abundant in the TME due to altered cancer metabolism, influence intercellular communication and mitochondrial dynamics in GBM. We hypothesized that specific post-translational modifications (PTMs), driven by these metabolites, regulate mitochondrial homeostasis and function, thereby promoting tumor progression. To test this hypothesis, we employed a range of experimental procedures. Co-culture systems were established to model the interaction between GBM cells and stromal cells within the TME. We utilized flow cytometry to analyze cellular characteristics and interactions, while Western blotting and immunofluorescence were used to examine protein expression, localization, and PTMs. Functional assays, including various commercial kits, were performed to assess mitochondrial biology. Bioinformatics analyses were conducted to identify potential molecular pathways involved, and these findings were validated in vivo using animal models. Our unpublished data reveal that an abnormal increase in a specific tumor metabolite leads to the PTM of key proteins. This modification alters the function and expression of these proteins, resulting in heightened interaction between GBM cells and stromal cells. Consequently, we observed an enhancement of mitochondrial-related biological functions within the GBM cells, which ultimately fuels tumor progression. In conclusion, our findings demonstrate that metabolic byproducts in the GBM microenvironment act as signaling molecules, effectively "hijacking" normal stromal cells to support the mitochondrial homeostasis and growth of the tumor. This novel mechanism of intercellular communication presents a potential new axis in GBM pathophysiology, offering promising therapeutic targets to disrupt tumor progression and improve patient outcomes. Citation Format: Zhongsheng You, Karrie Kiang, Gilberto Leung. Metabolite-driven post-translational modifications regulate mitochondrial homeostasis in the glioblastoma microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3368.