307. Metabolic heterogeneity among Glioblastoma stem-like cells reflects differences in response to drug treatments

Abstract

Purpose Glioblastoma multiforme (GBM) is the most aggressive brain tumor. The cancer stem cell hypothesis postulates the existence within GBM of a small fraction of self-renewing cells with stem like properties (GSCs), resistant to conventional treatments. Metabolic profiling may contribute to discover new diagnostic or prognostic biomarkers to be used for personalized therapies. Methods Forty-four GSC lines, derived from GBM patients were analyzed via MR spectroscopy as described in [1] . Unsupervised Cluster analysis of MR data was performed to identify GSC subgroups with different metabolic profiles. Responses to treatment with oligomycin and etomoxir were examined by MRS and confocal microscopy. Results Clustering of GSCs evidenced three subgroups: Clusters 1a and 1b, with high intergroup similarity and neural fingerprints, and Cluster 2, with a metabolism typical of commercial tumor lines (Fig. 1) according to [2] . Subclones generated by the same GSC line showed different metabolic phenotypes. Aerobic glycolysis prevailed in Cluster 2 cells as demonstrated by higher lactate production compared to Cluster 1 cells. Oligomycin, a mitochondrial ATPase inhibitor, induced high lactate extrusion only in Cluster 1 cells, where it produced neutral lipid accumulation detected as mobile lipid signals (MRS) and as lipid droplets (confocal microscopy). Conclusions These results indicate a relevant role of mitochondrial fatty acids oxidation for energy production in GSCs. On the other hand, further metabolic differences, likely accounting for different therapy responsiveness observed after etomoxir treatment, suggest that caution must be used in considering patient treatment with mitochondria FAO blockers.