Efficient mitochondrial glutamine targeting prevails over glioblastoma metabolic plasticity.

Purpose Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer, however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof-of concept for personalized metabolic targeting of GBM. <p>Experimental Design We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays and mitochondrial respirometry.</p> <p>Results We found that metabolic phenotyping clearly identifies 2 clusters, GLN^High and GLN^Low, mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLN^High GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLN^High cultures are CD133^neg and display a mesenchymal signature in contrast to CD133^pos GLN^Low GBM cells.</p> <p>Conclusions Our results show that metabolic phenotyping identified an essential metabolic pathway ina GBM cell subtype, and provide a proof-of-concept for theranostic metabolic targeting.

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