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

Abstract

PurposeThis study aims to investigate Glioblastoma (GBM) cellular response to adhesion and metabolic inhibitors in the context of cells migration and cell-matrix adhesion properties. GBM is the most common incurable brain tumour. Decades of work into GBM chemical and molecular classification have identified mechanisms of drug resistance. Inhibitors targeting cancer cell migration and proliferation rarely take into consideration the heterogeneous migration property amongst cells, which may impact patients response to treatment. MethodsTissue samples were obtained from spatially distinct locations with different 5-aminolevulinic acid (5-ALA) fluorescent intensities, strong strongly fluorescent tumour cores, a weak fluorescent tumour rim, and nonfluorescent tumour margins. Samples were previously shown to be associated with different motility and adhesion properties. We tested tumour cells response to adhesion and metabolic inhibitors using metabolic assays. Cell survival was also monitored using time-lapse microscopy, while cultured on low-modulus polydimethylsiloxane representative of the stiffness of brain tissue. ResultsMetabolic viability assays, MTT and Cell Titer, showed substantial heterogeneity in drug potency. Highly fluorescent tumour core cells were significantly more resistant to an F0F1 ATP synthase inhibitor (Gboxin), and a FAK inhibitor (GSK2256098), and cell proliferation ceased post-treatment in vitro. Cells derived from non-fluorescent tumour margins exhibited higher potency for the ATP synthase inhibitor (Gboxin). However, cell proliferation persisted post-treatment. ConclusionOur study suggests that the adhesive and migration properties of cells account for the sensitivity to therapeutics in different regions of the tumour in individual patients and between patients with GBM.