Abstract 3829: Microenvironmental stiffness induces metabolic reprogramming in glioblastoma

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Abstract Glioblastoma (GBM) is the most common and lethal type of brain cancer with 5-year survival of <15%. The unique microenvironment of GBM is a key factor in tumor aggression. Similar to other solid tumors, GBM cells experience different biomechanical forces than do cells in healthy brain tissue. Here, we use atomic force microscopy to perform micro-compression mechanical analysis of xenografted GBM tumors. We show that tumors have a relatively stiff core (5-6 kPa Young’s modulus) and a softer edge (1-2 kPa Young’s modulus), yet all tumor tissue was stiffer than adjacent brain tissue (0.5-0.8 kPa Young’s modulus). To understand the functional implications of this biomechanical landscape, GBM spheroids were encapsulated in 3D culture matrices tuned to mimic the measured stiffnesses of a tumor regions and neighboring, non-cancerous tissue. These 3D matrices are fabricated from hyaluronic acid to promote GBM/matrix interaction through CD44 and RHAMM. RNA-sequencing analysis revealed overexpression of mitochondrial-encoded genes in stiff conditions, specifically genes encoding proteins involved in oxidation phosphorylation (OXPHOS), when compared to soft hydrogels. Using fluorescence-life time imaging microscopy to assess metabolic states at a single-cell level, we found that metabolism in GBM cells cultured in stiff matrices was dominated by OXPHOS while those in softer matrices was dominated by glycolysis (GLY). Furthermore, we show that this stiffness-induced shift towards OXPHOS in stiff matrices was associated with increased proliferation while the shift towards GLY in soft matrices was associated with increased migratory activity. Finally, inhibition of ezrin, an adaptor molecule linking the HA receptor CD44 to the actin cytoskeleton, eliminated the shift towards GLY induced in soft matrices, indicating that HA-CD44 interactions are necessary for these matrix-induced metabolic shifts. Citation Format: Alireza Sohrabi, Austin Lefebvre, Michael Condro, Harley Kornblum, Michelle Digman, Stephanie Seidlits. Microenvironmental stiffness induces metabolic reprogramming in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3829.