Differential response of patient-derived primary glioblastoma cells to metabolic and adhesion inhibitors

Abstract

Abstract This study aims to investigate the cellular response of Glioblastoma (GBM) to adhesion and metabolic inhibitors, focusing on cell migration and matrix adhesion properties. GBM is the most common incurable brain tumor. Despite decades of research into GBM’s chemical and molecular classification, identifying mechanisms of drug resistance has been challenging. Studies on inhibitors targeting cancer cell migration and proliferation rarely consider the heterogeneous migration properties among cells, which may impact patient responses to treatment. In this work, tissue samples were obtained from spatially distinct locations with different 5-aminolevulinic acid (5-ALA) fluorescent intensities—including strongly fluorescent tumor cores, a weakly fluorescent tumor rim, and non-fluorescent tumor margins. These samples were previously shown to be associated with significantly different motility and adhesion properties. We tested the response of tumor cells to adhesion and metabolic inhibitors using metabolic MTT and Cell Titer Glo viability assays, respectively. We also monitored cell survival using time-lapse microscopy, while culturing them on low-modulus polydimethylsiloxane (representing the stiffness of brain tissue). Metabolic viability assays revealed substantial heterogeneity in drug potency across cells from different regions of the tumor. Highly fluorescent tumor core cells were significantly more resistant to an F0F1 ATP synthase inhibitor (Gboxin), and a FAK inhibitor (GSK2256098), while their proliferation ceased post-treatment in vitro. In contrast, cells derived from non-fluorescent tumor margins exhibited higher potency for the ATP synthase inhibitor (Gboxin), but their proliferation persisted post-treatment. Our study demonstrates a correlation between the adhesive and migration properties of cells and their sensitivity to therapeutics in different regions of the tumor within individual patients and between patients with GBM.