Metabolic functions of astrocytes are retained by glioblastoma stem-like cells and support glioblastoma growth in vivo


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Tobias Ackermann1,Maria Francesca Allega2,Anaïs Oudin3,Anna Golebiewska3,Olivier Keunen3,Simone P. Niclou3,Eyal Gottlieb2,Saverio Tardito2
1Cancer Research UK Beatson Institute,2Oncometabolism Laboratory, Cancer Research UK Beatson Institute,3NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health

Abstract

Background

In the brain glutamine serves as a precursor for the neurotransmitter glutamate. The neuron-released glutamate is cleared from the synapsis by astrocytes which convert it to glutamine via glutamine synthetase (GS). Thus, glutamine-glutamate metabolism is essential for brain’s normal function.

Method

Results

Glioblastoma, the most common and aggressive form of brain cancer, expresses GS at levels comparable to that of astrocytes. Consistently, we found that that naïve glioblastoma cells cultured in serum-free and physiologically relevant conditions, avidly uptake and consume glutamate from the extracellular environment and express high levels of GS, resembling normal astrocytes. To test if glutamine synthesis is advantageous for tumour growth we generated patient-derived orthotropic glioblastoma xenografts stably expressing a shRNA against GS. Upon GS knock down we detected a significant reduction in tumour volume and an extension in the survival of mice, which substantiate pro-tumorigenic role of GS in glioblastoma. Moreover we observed that at clinical endpoint all the tumours re-gained GS expression by selectively suppressing the expression of the targeting shRNA.  

Conclusion

While this further corroborated the selective advantage conferred by GS expression in GBM cells, it prevented us to directly address the metabolic role GS in tumours. To this aim we developed a novel inducible lentiviral system encoding for miRNA targeting specifically GS as well as iRFP (infra-red fluorescent protein) and luciferase. This model will allow us to investigate which metabolic reactions downstream of GS-derived glutamine, support glioblastoma growth in vivo. This may lead to the identification of new therapeutic targets, which extend beyond the normal role of GS in neurophysiology.