Glioblastoma (GBM) remains the most common and aggressive malignant brain tumor in adults, whose lethality is driven by its invasive nature with substantial infiltration throughout the brain parenchyma. Yet, the reason why GBM grows so fast and aggressively is still highly debated. The importance of the substrate stiffness has been shown to play a major role in cell behavior. Here, we investigated the mechanisms underlying tumor invasivity and the GBM microenvironment. We show a differential response to substrate stiffness as a result of a ‘catch-bond’ mechanism that leads to better adhesion of cells contingent to the stiffness. We thus analysed mechanisms of EGF dependent signaling in terms of its interrelations with energy metabolism and reactive oxygen species (ROS) production, confirming a collaborative ROS/EGFR-dependent signaling augmenting GBM cells’ invasiveness. Further characterization of these intracellular pathways may provide candidates for new therapeutic strategies and targets as well as biomarkers for this aggressive disease.