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.

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Acknowledgements

We appreciate mass spectrometry analysis by R. Zhang, flow cytometry assistance by C. Shemo and S. O'Bryant, the glioblastoma tissue provided by M. McGraw and the Cleveland Clinic Tissue Procurement Service, and the IN528 model from I. Nakano at Ohio State University. We thank T. Roberts, J. Suh, G. Narla and members of the Rich laboratory for discussions. This work was supported by funding from National Institutes of Health grants CA197718, CA154130, CA169117, CA171652, NS087913 and NS089272 (J.N.R.), CA184090, NS091080 (S.B.) and CA168997, CA193256, CA201963 (J.W.L.); the James S. McDonnell Foundation (J.N.R.); the Research Programs Committees of the Cleveland Clinic (J.N.R. and K.Y.); Clinical and Translational Science Collaborative of Cleveland grant UL1TR000439 from the National Center for Advancing Translational Sciences (J.N.R. and K.Y.); a P&F grant from NIH Resource Center for Stable Isotope Resolved Metabolomics (RC-SIRM) at University of Kentucky (J.N.R. and K.Y.); and an ENGAGE grant from the National Center for Regenerative Medicine (K.Y.).

Author information

Author notes

    • Xiuxing Wang
    •  & Kailin Yang

    These authors contributed equally to this work.

Affiliations

  1. Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.

    • Xiuxing Wang
    • , Kailin Yang
    • , Qi Xie
    • , Qiulian Wu
    • , Stephen C Mack
    • , Yu Shi
    • , Leo J Y Kim
    • , Briana C Prager
    • , William A Flavahan
    • , Christopher G Hubert
    • , Tyler E Miller
    • , Wenchao Zhou
    • , Zhi Huang
    • , Xiaoguang Fang
    • , Shideng Bao
    •  & Jeremy N Rich
  2. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.

    • Kailin Yang
    • , Briana C Prager
    •  & Jeremy N Rich
  3. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, The Third Military Medical University, and The Key Laboratory of Tumor Immunopathology, The Ministry of Education of China, Chongqing, China.

    • Yu Shi
  4. Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.

    • Xiaojing Liu
    •  & Jason W Locasale
  5. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Meromit Singer
    • , Aviv Regev
    •  & Mario L Suvà
  6. Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Mario L Suvà
  7. Department of Quantitative Health Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.

    • Tae Hyun Hwang

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Contributions

X.W., K.Y. and J.N.R. designed the experiments, analyzed the data and wrote the manuscript with contributions from all authors. X.W., K.Y., Q.X., Q.W., S.C.M., C.G.H., T.E.M., W.Z., Z.H. and X.F. performed the experiments. K.Y., Y.S., L.J.Y.K., B.C.P., W.A.F., M.S., A.R., M.L.S. and T.H.H. performed database analyses. X.W., K.Y., Q.X., X.L. and J.W.L. performed metabolic experiments. S.B. provided scientific input and helped edit the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jeremy N Rich.

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https://doi.org/10.1038/nn.4537

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