The Biomechanics of Glioblastoma: Why Glioblastoma Models and Clinical Reality Diverge

Glioblastomas (GB) are highly aggressive brain tumors with poor patient prognosis and low survival rates. To identify novel therapeutic targets, the tumor microenvironment (TME) is increasingly examined, with a particular focus on biomechanical changes in the extracellular matrix (ECM) that contribute to GB aggressiveness. In GB, the ECM stiffens, regulating cell behavior through mechanotransduction. Preclinical in vitro and ex vivo studies generally report increased stiffness in GB relative to healthy brain tissue, whereas clinical in vivo measurements often report decreased stiffness. This review examines potential causes for this discrepancy, highlighting both biological and technical factors. Preclinical measurements are frequently performed using atomic force microscopy (AFM), while clinical stiffness is assessed via magnetic resonance elastography (MRE). Differences in methodology, including sample preparation, measurement modalities, and spatial scale, partly explain divergent stiffness values. Biological factors such as necrosis, edema, and physical confinement by the skull, which are preserved only in vivo, also contribute to these differences. To reconcile these findings, future research should employ physiologically relevant in vitro models that better replicate in vivo GB biomechanics, together with high-throughput and accurate animal models. Integrating these approaches may clarify the biomechanical landscape of GB and result in more effective therapeutic strategies.