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. Locasale & 2 others Shideng Bao, Jeremy N. Rich

Research output: Contribution to journalArticle

24 Citations (Scopus)

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

Fingerprint

Neoplastic Stem Cells
Brain Neoplasms
Glioma
Maintenance
Enzymes
Purine Nucleotides
Glucose
Neoplasms
Glioblastoma
purine
Neurons
Therapeutics
Growth

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Wang, X., Yang, K., Xie, Q., Wu, Q., Mack, S. C., Shi, Y., ... 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

Purine synthesis promotes maintenance of brain tumor initiating cells in glioma. / Wang, Xiuxing; Yang, Kailin; Xie, Qi; Wu, Qiulian; Mack, Stephen C.; Shi, Yu; Kim, Leo J.Y.; Prager, Briana C.; Flavahan, William A.; Liu, Xiaojing; Singer, Meromit; Hubert, Christopher G.; Miller, Tyler E.; Zhou, Wenchao; Huang, Zhi; Fang, Xiaoguang; Regev, Aviv; Suvà, Mario L.; Hwang, Tae Hyun; Locasale, Jason W.; Bao, Shideng; Rich, Jeremy N.

In: Nature Neuroscience, Vol. 20, No. 5, 01.05.2017, p. 661-673.

Research output: Contribution to journalArticle

Wang, X, Yang, K, Xie, Q, Wu, Q, Mack, SC, Shi, Y, Kim, LJY, Prager, BC, Flavahan, WA, Liu, X, Singer, M, Hubert, CG, Miller, TE, Zhou, W, Huang, Z, Fang, X, Regev, A, Suvà, ML, Hwang, TH, Locasale, JW, Bao, S & Rich, JN 2017, 'Purine synthesis promotes maintenance of brain tumor initiating cells in glioma', Nature Neuroscience, vol. 20, no. 5, pp. 661-673. https://doi.org/10.1038/nn.4537
Wang, Xiuxing ; Yang, Kailin ; Xie, Qi ; Wu, Qiulian ; Mack, Stephen C. ; Shi, Yu ; Kim, Leo J.Y. ; Prager, Briana C. ; Flavahan, William A. ; Liu, Xiaojing ; Singer, Meromit ; Hubert, Christopher G. ; Miller, Tyler E. ; Zhou, Wenchao ; Huang, Zhi ; Fang, Xiaoguang ; Regev, Aviv ; Suvà, Mario L. ; Hwang, Tae Hyun ; Locasale, Jason W. ; Bao, Shideng ; Rich, Jeremy N. / Purine synthesis promotes maintenance of brain tumor initiating cells in glioma. In: Nature Neuroscience. 2017 ; Vol. 20, No. 5. pp. 661-673.
@article{cd76deb192024e33abee2542fa6fce19,
title = "Purine synthesis promotes maintenance of brain tumor initiating cells in glioma",
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.",
author = "Xiuxing Wang and Kailin Yang and Qi Xie and Qiulian Wu and Mack, {Stephen C.} and Yu Shi and Kim, {Leo J.Y.} and Prager, {Briana C.} and Flavahan, {William A.} and Xiaojing Liu and Meromit Singer and Hubert, {Christopher G.} and Miller, {Tyler E.} and Wenchao Zhou and Zhi Huang and Xiaoguang Fang and Aviv Regev and Suv{\`a}, {Mario L.} and Hwang, {Tae Hyun} and Locasale, {Jason W.} and Shideng Bao and Rich, {Jeremy N.}",
year = "2017",
month = "5",
day = "1",
doi = "10.1038/nn.4537",
language = "English (US)",
volume = "20",
pages = "661--673",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Purine synthesis promotes maintenance of brain tumor initiating cells in glioma

AU - Wang, Xiuxing

AU - Yang, Kailin

AU - Xie, Qi

AU - Wu, Qiulian

AU - Mack, Stephen C.

AU - Shi, Yu

AU - Kim, Leo J.Y.

AU - Prager, Briana C.

AU - Flavahan, William A.

AU - Liu, Xiaojing

AU - Singer, Meromit

AU - Hubert, Christopher G.

AU - Miller, Tyler E.

AU - Zhou, Wenchao

AU - Huang, Zhi

AU - Fang, Xiaoguang

AU - Regev, Aviv

AU - Suvà, Mario L.

AU - Hwang, Tae Hyun

AU - Locasale, Jason W.

AU - Bao, Shideng

AU - Rich, Jeremy N.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85016134979&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016134979&partnerID=8YFLogxK

U2 - 10.1038/nn.4537

DO - 10.1038/nn.4537

M3 - Article

VL - 20

SP - 661

EP - 673

JO - Nature Neuroscience

JF - Nature Neuroscience

SN - 1097-6256

IS - 5

ER -