Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3

Ping Mao, Kaushal Joshi, Jianfeng Li, Sung Hak Kim, Peipei Li, Lucas Santana-Santos, Soumya Luthra, Uma R. Chandran, Panayiotis V. Benos, Luke Smith, Maode Wang, Bo Hu, Shi Yuan Cheng*, Robert W. Sobol, Ichiro Nakano

*Corresponding author for this work

Research output: Contribution to journalArticle

270 Citations (Scopus)

Abstract

Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and downregulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3- mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.

Original languageEnglish (US)
Pages (from-to)8644-8649
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number21
DOIs
StatePublished - May 21 2013

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Aldehyde Dehydrogenase
Mesenchymal Stromal Cells
Glioma
Stem Cells
Radiation

Keywords

  • Cancer stem cell
  • Epithelial-to-mesenchymal transition
  • Glioblastoma
  • Glioblastoma multiforme
  • Proneural-to-mesenchymal transition

ASJC Scopus subject areas

  • General

Cite this

Mao, Ping ; Joshi, Kaushal ; Li, Jianfeng ; Kim, Sung Hak ; Li, Peipei ; Santana-Santos, Lucas ; Luthra, Soumya ; Chandran, Uma R. ; Benos, Panayiotis V. ; Smith, Luke ; Wang, Maode ; Hu, Bo ; Cheng, Shi Yuan ; Sobol, Robert W. ; Nakano, Ichiro. / Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 21. pp. 8644-8649.
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title = "Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3",
abstract = "Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and downregulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3- mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.",
keywords = "Cancer stem cell, Epithelial-to-mesenchymal transition, Glioblastoma, Glioblastoma multiforme, Proneural-to-mesenchymal transition",
author = "Ping Mao and Kaushal Joshi and Jianfeng Li and Kim, {Sung Hak} and Peipei Li and Lucas Santana-Santos and Soumya Luthra and Chandran, {Uma R.} and Benos, {Panayiotis V.} and Luke Smith and Maode Wang and Bo Hu and Cheng, {Shi Yuan} and Sobol, {Robert W.} and Ichiro Nakano",
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Mao, P, Joshi, K, Li, J, Kim, SH, Li, P, Santana-Santos, L, Luthra, S, Chandran, UR, Benos, PV, Smith, L, Wang, M, Hu, B, Cheng, SY, Sobol, RW & Nakano, I 2013, 'Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 21, pp. 8644-8649. https://doi.org/10.1073/pnas.1221478110

Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. / Mao, Ping; Joshi, Kaushal; Li, Jianfeng; Kim, Sung Hak; Li, Peipei; Santana-Santos, Lucas; Luthra, Soumya; Chandran, Uma R.; Benos, Panayiotis V.; Smith, Luke; Wang, Maode; Hu, Bo; Cheng, Shi Yuan; Sobol, Robert W.; Nakano, Ichiro.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 21, 21.05.2013, p. 8644-8649.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3

AU - Mao, Ping

AU - Joshi, Kaushal

AU - Li, Jianfeng

AU - Kim, Sung Hak

AU - Li, Peipei

AU - Santana-Santos, Lucas

AU - Luthra, Soumya

AU - Chandran, Uma R.

AU - Benos, Panayiotis V.

AU - Smith, Luke

AU - Wang, Maode

AU - Hu, Bo

AU - Cheng, Shi Yuan

AU - Sobol, Robert W.

AU - Nakano, Ichiro

PY - 2013/5/21

Y1 - 2013/5/21

N2 - Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and downregulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3- mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.

AB - Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and downregulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3- mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.

KW - Cancer stem cell

KW - Epithelial-to-mesenchymal transition

KW - Glioblastoma

KW - Glioblastoma multiforme

KW - Proneural-to-mesenchymal transition

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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