Aggressive Glioblastoma Cells Enhance the Migratory Persistence and Velocity of Less Aggressive Cells to Promote Tumor Dissemination

Abstract

Glioblastoma multiforme (GBM) is a highly lethal brain cancer driven by aggressive invasion. Epidermal growth factor receptor (EGFR) is frequently amplified in GBM, with the EGFRvIII mutant enhancing the infiltrative features of EGFRwt-overexpressing cells. Previously, we identified Src as a key cell-cell communication mediator between EGFRvIII and EGFRwt cells. However, a quantitative biophysical characterization of how EGFRvIII induces this increased infiltration, specifically detailing altered movement parameters and the underlying mechanisms, remains lacking. Using bulk cell culture and 2-cell microfluidic chips, we quantitatively analyzed the motility of EGFRwt-overexpressing and EGFRvIII-expressing GBM cells. We observed that EGFRvIII cells exhibit higher migration velocity and persistence compared to EGFRwt cells, with a highly persistent subpopulation contributing significantly to these differences. Notably, the co-culture of EGFRvIII cells enhanced the velocity and migration persistence of EGFRwt-overexpressing cells, leading to increased spreading. Our findings revealed that Src-mediated cell-cell communication from EGFRvIII-expressing to EGFRwt-overexpressing cells promotes aggressive GBM spreading by increasing both their velocity and migration persistence at the micro-environmental level. Inhibiting the Src pathway with dasatinib reversed this pro-migratory effect, markedly reducing their migration persistence. These insights refine our understanding of GBM infiltration and highlight Src inhibition as a promising strategy in EGFRvIII-positive tumors.