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Altered cellular metabolism in gliomas — an emerging landscape of actionable co-dependency targets

Abstract

Altered cellular metabolism is a hallmark of gliomas. Propelled by a set of recent technological advances, new insights into the molecular mechanisms underlying glioma metabolism are rapidly emerging. In this Review, we focus on the dynamic nature of glioma metabolism and how it is shaped by the interaction between tumour genotype and brain microenvironment. Recent advances integrating metabolomics with genomics are discussed, yielding new insight into the mechanisms that drive glioma pathogenesis. Studies that shed light on interactions between the tumour microenvironment and tumour genotype are highlighted, providing important clues as to how gliomas respond to and adapt to their changing tissue and biochemical contexts. Finally, a road map for the discovery of potential new glioma drug targets is suggested, with the goal of translating these new insights about glioma metabolism into clinical benefits for patients.

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Fig. 1: Glioma nutrient uptake and utilization.
Fig. 2: RTK signalling regulates glioma metabolism.
Fig. 3: Glioma IDH mutations define metabolic dependencies.
Fig. 4: A roadmap for finding actionable metabolic dependencies in malignant gliomas.
Fig. 5: An expanded pharmacopoeia of metabolic drug targets in malignant glioma.

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Acknowledgements

This work was supported by the Ludwig Institute for Cancer Research and by grants from the National Institute for Neurological Diseases and Stroke (NS73831), the Defeat GBM Program of the National Brain Tumour Society, and the Ben and Catherine Ivy Foundation, as well as by an award from the Sharpe/National Brain Tumour Society Research Program and a Compute for the Cure Award from the Nvidia Foundation (to P.S.M.).

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P.S.M., J.B., S.W. and S.C. researched data for the article, contributed to the discussion of content, wrote the article and reviewed or edited the manuscript before submission. W.Z. contributed to the discussion of content and the writing of the article. K.M. researched data for the article, contributed to the discussion of content and reviewed or edited the manuscript before submission.

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Correspondence to Paul S. Mischel.

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P.S.M. is a co-founder of Boundless Bio, Inc. He has equity and serves as a consultant for the company. P.S.M. also did a one-time consultation for Abide Therapeutics, Inc. The other authors declare no competing interests.

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Nature Reviews Cancer thanks S. Venneti, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Gliomas

Tumours that arise within the brain and resemble the constituent glial cells. They are classified histologically as astrocytomas, oligodendrogliomas or ependymomas and are now also classified on the basis of molecular features.

Glioblastoma

(GBM). The most aggressive form of glioma, often referred to as grade IV astrocytoma.

Metabolic flux

The turnover rate of a metabolite, which is determined by the rates of the forward and reverse reactions in a metabolic pathway.

Acetate

A two-carbon molecule that can react with coenzyme A in the presence of ATP to generate acetyl-CoA.

Receptor tyrosine kinase

(RTK). A class of transmembrane cell surface receptors for ligands including growth factors, cytokines and hormones, to propagate kinase-cascading signalling.

MYC

Family of proto-oncogenes that encode transcription factors that regulate a wide range of biological functions, including cell proliferation and metabolism. In the human genome, it consists of three members: c-MYC (MYC), L-MYC (MYCL) and N-MYC (MYCN).

Phosphatidylcholine

A class of phospholipids with a choline head group; a major lipid component of cell membranes.

Metabolic dependencies

Reliance on a metabolite or metabolic pathway for survival.

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Bi, J., Chowdhry, S., Wu, S. et al. Altered cellular metabolism in gliomas — an emerging landscape of actionable co-dependency targets. Nat Rev Cancer 20, 57–70 (2020). https://doi.org/10.1038/s41568-019-0226-5

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