Abstract 5110: Solid stress reduces synaptic density and neuronal activity via hypoxia-induced reactive gene expression programs in glioblastoma

Abstract Mass effect in central nervous system pathologies poses a significant clinical challenge. This phenomenon, characterized by the compression and deformation of neural tissue from space-occupying lesions, can lead to debilitating neurological symptoms. In glioblastoma, we have shown previously that compressive solid stresses from the growing tumor are correlated with significantly worse neurological performance and survival in patients. While edema is often measured as a prognostic biomarker, it fails to consistently predict neurological deficits; conversely, solid stress correlates with functional impairments and reduced cerebral blood flow. In this study, we explored the direct effects of solid stress on human induced pluripotent stem cell (hiPSC)-derived neurons using an in vitro compression system. Our results reveal that solid stress decreases synaptic puncta and neuronal excitability by activating hypoxia response and pro-apoptotic programs in neurons. We further show that compression upregulates reactive gene expression programs in astrocytes and microglia, contributing to neuroinflammation. These findings illuminate the critical role of solid stress in glioblastoma, offering new insights into its potential contribution to neurodegeneration. Citation Format: Maksym Zarodniuk, Anna Wenninger, Jihaeng Lee, Julian Najera, Jack Markillie, Bianca Batista, Christopher Patzke, Meenal Datta. Solid stress reduces synaptic density and neuronal activity via hypoxia-induced reactive gene expression programs in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5110.