Purine synthesis promotes maintenance of brain tumor initiating cells in glioma

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

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)661-673
Number of pages13
JournalNature Neuroscience
Volume20
Issue number5
DOIs
StatePublished - May 1 2017

ASJC Scopus subject areas

  • Neuroscience(all)

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    Wang, X., Yang, K., Xie, Q., Wu, Q., Mack, S. C., Shi, Y., Kim, L. J. Y., Prager, B. C., Flavahan, W. A., Liu, X., Singer, M., Hubert, C. G., Miller, T. E., Zhou, W., Huang, Z., Fang, X., Regev, A., Suvà, M. L., Hwang, T. H., ... Rich, J. N. (2017). Purine synthesis promotes maintenance of brain tumor initiating cells in glioma. Nature Neuroscience, 20(5), 661-673. https://doi.org/10.1038/nn.4537