Journal article
Purine synthesis promotes maintenance of brain tumor initiating cells in glioma
Nature neuroscience, Vol.20(5), pp.661-673
05/01/2017
DOI: 10.1038/nn.4537
PMCID: PMC6015494
PMID: 28346452
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.
Details
- Title: Subtitle
- Purine synthesis promotes maintenance of brain tumor initiating cells in glioma
- Creators
- Xiuxing Wang - Cleveland Clinic Lerner College of MedicineKailin Yang - Cleveland Clinic Lerner College of MedicineQi Xie - Cleveland Clinic Lerner College of MedicineQiulian Wu - Cleveland Clinic Lerner College of MedicineStephen C. Mack - Cleveland Clinic Lerner College of MedicineYu Shi - Cleveland Clinic Lerner College of MedicineLeo J. Y. Kim - Cleveland Clinic Lerner College of MedicineBriana C. Prager - Cleveland Clinic Lerner College of MedicineWilliam A. Flavahan - Cleveland Clinic Lerner College of MedicineXiaojing Liu - Duke Medical CenterMeromit Singer - Broad InstituteChristopher G. Hubert - Cleveland Clinic Lerner College of MedicineTyler E. Miller - Cleveland Clinic Lerner College of MedicineWenchao Zhou - Cleveland Clinic Lerner College of MedicineZhi Huang - Cleveland Clinic Lerner College of MedicineXiaoguang Fang - Cleveland Clinic Lerner College of MedicineAviv Regev - Broad InstituteMario L. Suva - Broad InstituteTae Hyun Hwang - Cleveland Clinic Lerner College of MedicineJason W. Locasale - Duke Medical CenterShideng Bao - Cleveland Clinic Lerner College of MedicineJeremy N. Rich - Cleveland Clinic Lerner College of Medicine
- Resource Type
- Journal article
- Publication Details
- Nature neuroscience, Vol.20(5), pp.661-673
- Publisher
- Springer Nature
- DOI
- 10.1038/nn.4537
- PMID
- 28346452
- PMCID
- PMC6015494
- ISSN
- 1097-6256
- eISSN
- 1546-1726
- Number of pages
- 15
- Grant note
- James S. McDonnell Foundation P&F grant from NIH Resource Center for Stable Isotope Resolved Metabolomics (RC-SIRM) at University of Kentucky Research Programs Committees of the Cleveland Clinic ENGAGE grant from the National Center for Regenerative Medicine CA197718; CA154130; CA169117; CA171652; NS087913; NS089272; CA184090; NS091080; CA168997; CA193256; CA201963 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA UL1TR000439 / Clinical and Translational Science Collaborative of Cleveland grant from the National Center for Advancing Translational Sciences T32GM007250 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01CA154130 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1TR000439 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) R01NS089272 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
- Language
- English
- Date published
- 05/01/2017
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696721802771
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