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

doi:10.1016/j.celrep.2023.113175

Microenvironmental stiffness induces metabolic reprogramming in glioblastoma

Cell Rep. 2023 Oct 31;42(10):113175. doi: 10.1016/j.celrep.2023.113175. Epub 2023 Sep 26.

Affiliations

¹ 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.
² Department of Biomedical Engineering, University of California at Irvine, Irvine, CA 92697, USA.
³ Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
⁴ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ 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. Electronic address: seidlits@utexas.edu.

Abstract

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.

Keywords: CP: Cancer; CP: Metabolism; extracellular matrix; tissue mechanics.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / metabolism
Brain Neoplasms* / metabolism
Cell Line, Tumor
Glioblastoma* / pathology
Humans
Mice
Tumor Microenvironment

Grants and funding

R01 CA241927/CA/NCI NIH HHS/United States