Microenvironmental stiffness induces metabolic reprogramming in glioblastoma
Alireza Sohrabi,
Austin E.Y.T. Lefebvre,
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. Seidlits
Affiliations
Alireza Sohrabi
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
Austin E.Y.T. Lefebvre
Department of Biomedical Engineering, University of California at Irvine, Irvine, CA 92697, USA
Mollie J. Harrison
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
Michael C. Condro
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Talia M. Sanazzaro
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
Gevick Safarians
Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
Itay Solomon
Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
Soniya Bastola
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Shadi Kordbacheh
Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
Nadia Toh
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
Harley I. Kornblum
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Michelle A. Digman
Department of Biomedical Engineering, University of California at Irvine, Irvine, CA 92697, USA
Stephanie K. Seidlits
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author
Summary: The mechanical properties of solid tumors influence tumor cell phenotype and the ability to invade 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 peritumoral brain tissues, but tumor stiffness is heterogeneous where tumor edges are softer than the tumor core. We then developed 3D scaffolds with μ-compressive moduli resembling either stiffer tumor core or softer peritumoral 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.
