Journal Article

Purine synthesis promotes maintenance of brain tumor initiating cells in glioma

Bao, Shideng, Locasale, Jason W, Hubert, Christopher G, Hwang, Tae Hyun, Regev, Aviv, Wu, Qiulian, Flavahan, William A, Suvà, Mario L, Fang, Xiaoguang, Rich, Jeremy N, Miller, Tyler E, Yang, Kailin, Kim, Leo J Y, Xie, Qi, Prager, Briana C, Huang, Zhi, Zhou, Wenchao, Liu, Xiaojing, Wang, Xiuxing, Shi, Yu, Mack, Stephen C, Singer, Meromit

2017

Overview

Brain tumor initiating cells (BTICs) utilize high-affinity glucose uptake, which is normally active in neurons to maintain energy demands and self-renew. Leveraging metabolomic and genomic analyses, Wang et al . report that de novo purine biosynthesis reprograms BTIC metabolism, revealing a potential point of fragility amenable to targeted cancer therapy. Brain tumor initiating cells (BTICs), also known as cancer stem cells, hijack high-affinity glucose uptake active normally in neurons to maintain energy demands. Here we link metabolic dysregulation in human BTICs to a nexus between MYC and de novo purine synthesis, mediating glucose-sustained anabolic metabolism. Inhibiting purine synthesis abrogated BTIC growth, self-renewal and in vivo tumor formation by depleting intracellular pools of purine nucleotides, supporting purine synthesis as a potential therapeutic point of fragility. In contrast, differentiated glioma cells were unaffected by the targeting of purine biosynthetic enzymes, suggesting selective dependence of BTICs. MYC coordinated the control of purine synthetic enzymes, supporting its role in metabolic reprogramming. Elevated expression of purine synthetic enzymes correlated with poor prognosis in glioblastoma patients. Collectively, our results suggest that stem-like glioma cells reprogram their metabolism to self-renew and fuel the tumor hierarchy, revealing potential BTIC cancer dependencies amenable to targeted therapy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 101/58 / 13/106 / 38/1 / 38/61 / 38/89 / 42/109 / 631/532/71 / 631/67/71 / 692/699/67/1922 / 96/100 / 96/31 / Adenosine Monophosphate - biosynthesis / Animal Genetics and Genomics / Behavioral Sciences / Biological Techniques / Biomedicine / Brain cancer / Brain research / Cancer therapies / Carbon / Cell Proliferation - physiology / Cells, Cultured / DNA methylation / Enzymes / Genomes / Genomics / Glioma - enzymology / Glioma - metabolism / Glucose / Glycolysis - physiology / Guanosine Monophosphate - biosynthesis / Humans / Hypoxia / Medical prognosis / Medical research / Medicine / Metabolism / Metabolites / Metabolomics / Mutation / Neoplastic Stem Cells - enzymology / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - physiology / Neurobiology / Neurosciences / Proto-Oncogene Proteins c-myc - metabolism / Purines - biosynthesis / Ribose-Phosphate Pyrophosphokinase - biosynthesis / Stem cells / Up-Regulation