Microenvironmental stiffness induces metabolic reprogramming in glioblastoma

• DOI: 10.1016/j.celrep.2023.113175
• Publication Date: 2023-09-26T16:21:16Z
• Authors: Alireza Sohrabi; Austin E.Y.T. Lef...; Mollie J. Harrison; Michael C. Condro; Talia M. Sanazzaro; Gevick Safarians; Itay Solomon; Soniya Bastola; Shadi Kordbacheh; Nadia Toh; Harley I. Kornblum; Michelle A. Digman; Stephanie K. Seid...
• Keywords: 570; QH301-705.5; extracellular matrix; Medical Physiology; 610; Bioengineering; Article; Cell Line; Mice; Rare Diseases; Cell Line, Tumor; Tumor Microenvironment; Humans; Animals; Biology (General); Cancer; Tumor; Brain Neoplasms; Neurosciences; Brain; Biological Sciences; CP: Metabolism; Brain Disorders; Brain Cancer; Biological sciences; tissue mechanics; Biochemistry and Cell Biology; Glioblastoma; CP: Cancer

AbstractThe mechanical properties of solid tumors influence tumor cell phenotype and ability to invade into surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peri-tumoral brain tissues, but tumor stiffness is heterogenous where tumor edges are softer than the tumor core. Then, we developed three-dimensional scaffolds with µ-compressive moduli resembling either stiffer, tumor core or softer, peri-tumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells.