Gene expression profiling distinguishes proneural glioma stem cells from mesenchymal glioma stem cells

Uma R. Chandran, Soumya Luthra, Lucas Santana-Santos, Ping Mao, Sung Hak Kim, Mutsuko Minata, Jianfeng Li, Panayiotis V. Benos, Mao DeWang, Bo Hu, Shi-Yuan Cheng, Ichiro Nakano, Robert W. Sobol*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 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. Previously we identified and characterized two mutually exclusive GSC subtypes with distinct activated signaling pathways and biological phenotypes. One GSC subtype presented with a gene signature resembling Proneural (PN) HGG, whereas the other was similar to mesenchymal (Mes) HGG. Classical HGG-derived GSCs were sub-classified as either one of these two subtypes. Differential mRNA expression analysis of PN and Mes GSCs identified 5796 differentially expressed genes, revealing 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. Expression of ALDH1A3 - one of the most up-regulated Mes representative genes and a universal cancer stem cell marker in non-brain cancers - was associated with self-renewal and a multi-potent stem cell population in Mes but not PN samples. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs in vitro. Lastly, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs in vitro. 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. Here, we describe the gene expression analysis, including pre-processing methods for the data published by Mao and colleagues in PNAS [1], integration of microarray data from this study with The Cancer Genome Atlas (TCGA) glioblastoma data and also with another published study.The raw CEL files and processed data were submitted to Gene Expression Omnibus (GEO) under the accession GSE67089.

Original languageEnglish (US)
Pages (from-to)333-336
Number of pages4
JournalGenomics Data
Volume5
DOIs
StatePublished - Sep 1 2015

Fingerprint

Gene Expression Profiling
Stem cells
Mesenchymal Stromal Cells
Gene expression
Glioma
Stem Cells
Genes
Radiation
Phenotype
Microarrays
Gene Expression
Neoplasms
Heterografts
Neoplastic Stem Cells
Atlases
Information Storage and Retrieval
Tumors
Glioblastoma

Keywords

  • Glioblastoma
  • Microarray
  • Normalization
  • The Cancer Genome Atlas Project

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Medicine
  • Genetics

Cite this

Chandran, U. R., Luthra, S., Santana-Santos, L., Mao, P., Kim, S. H., Minata, M., ... Sobol, R. W. (2015). Gene expression profiling distinguishes proneural glioma stem cells from mesenchymal glioma stem cells. Genomics Data, 5, 333-336. https://doi.org/10.1016/j.gdata.2015.07.007
Chandran, Uma R. ; Luthra, Soumya ; Santana-Santos, Lucas ; Mao, Ping ; Kim, Sung Hak ; Minata, Mutsuko ; Li, Jianfeng ; Benos, Panayiotis V. ; DeWang, Mao ; Hu, Bo ; Cheng, Shi-Yuan ; Nakano, Ichiro ; Sobol, Robert W. / Gene expression profiling distinguishes proneural glioma stem cells from mesenchymal glioma stem cells. In: Genomics Data. 2015 ; Vol. 5. pp. 333-336.
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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. Previously we identified and characterized two mutually exclusive GSC subtypes with distinct activated signaling pathways and biological phenotypes. One GSC subtype presented with a gene signature resembling Proneural (PN) HGG, whereas the other was similar to mesenchymal (Mes) HGG. Classical HGG-derived GSCs were sub-classified as either one of these two subtypes. Differential mRNA expression analysis of PN and Mes GSCs identified 5796 differentially expressed genes, revealing 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. Expression of ALDH1A3 - one of the most up-regulated Mes representative genes and a universal cancer stem cell marker in non-brain cancers - was associated with self-renewal and a multi-potent stem cell population in Mes but not PN samples. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs in vitro. Lastly, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs in vitro. 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. Here, we describe the gene expression analysis, including pre-processing methods for the data published by Mao and colleagues in PNAS [1], integration of microarray data from this study with The Cancer Genome Atlas (TCGA) glioblastoma data and also with another published study.The raw CEL files and processed data were submitted to Gene Expression Omnibus (GEO) under the accession GSE67089.",
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Chandran, UR, Luthra, S, Santana-Santos, L, Mao, P, Kim, SH, Minata, M, Li, J, Benos, PV, DeWang, M, Hu, B, Cheng, S-Y, Nakano, I & Sobol, RW 2015, 'Gene expression profiling distinguishes proneural glioma stem cells from mesenchymal glioma stem cells', Genomics Data, vol. 5, pp. 333-336. https://doi.org/10.1016/j.gdata.2015.07.007

Gene expression profiling distinguishes proneural glioma stem cells from mesenchymal glioma stem cells. / Chandran, Uma R.; Luthra, Soumya; Santana-Santos, Lucas; Mao, Ping; Kim, Sung Hak; Minata, Mutsuko; Li, Jianfeng; Benos, Panayiotis V.; DeWang, Mao; Hu, Bo; Cheng, Shi-Yuan; Nakano, Ichiro; Sobol, Robert W.

In: Genomics Data, Vol. 5, 01.09.2015, p. 333-336.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gene expression profiling distinguishes proneural glioma stem cells from mesenchymal glioma stem cells

AU - Chandran, Uma R.

AU - Luthra, Soumya

AU - Santana-Santos, Lucas

AU - Mao, Ping

AU - Kim, Sung Hak

AU - Minata, Mutsuko

AU - Li, Jianfeng

AU - Benos, Panayiotis V.

AU - DeWang, Mao

AU - Hu, Bo

AU - Cheng, Shi-Yuan

AU - Nakano, Ichiro

AU - Sobol, Robert W.

PY - 2015/9/1

Y1 - 2015/9/1

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. Previously we identified and characterized two mutually exclusive GSC subtypes with distinct activated signaling pathways and biological phenotypes. One GSC subtype presented with a gene signature resembling Proneural (PN) HGG, whereas the other was similar to mesenchymal (Mes) HGG. Classical HGG-derived GSCs were sub-classified as either one of these two subtypes. Differential mRNA expression analysis of PN and Mes GSCs identified 5796 differentially expressed genes, revealing 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. Expression of ALDH1A3 - one of the most up-regulated Mes representative genes and a universal cancer stem cell marker in non-brain cancers - was associated with self-renewal and a multi-potent stem cell population in Mes but not PN samples. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs in vitro. Lastly, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs in vitro. 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. Here, we describe the gene expression analysis, including pre-processing methods for the data published by Mao and colleagues in PNAS [1], integration of microarray data from this study with The Cancer Genome Atlas (TCGA) glioblastoma data and also with another published study.The raw CEL files and processed data were submitted to Gene Expression Omnibus (GEO) under the accession GSE67089.

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. Previously we identified and characterized two mutually exclusive GSC subtypes with distinct activated signaling pathways and biological phenotypes. One GSC subtype presented with a gene signature resembling Proneural (PN) HGG, whereas the other was similar to mesenchymal (Mes) HGG. Classical HGG-derived GSCs were sub-classified as either one of these two subtypes. Differential mRNA expression analysis of PN and Mes GSCs identified 5796 differentially expressed genes, revealing 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. Expression of ALDH1A3 - one of the most up-regulated Mes representative genes and a universal cancer stem cell marker in non-brain cancers - was associated with self-renewal and a multi-potent stem cell population in Mes but not PN samples. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs in vitro. Lastly, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs in vitro. 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. Here, we describe the gene expression analysis, including pre-processing methods for the data published by Mao and colleagues in PNAS [1], integration of microarray data from this study with The Cancer Genome Atlas (TCGA) glioblastoma data and also with another published study.The raw CEL files and processed data were submitted to Gene Expression Omnibus (GEO) under the accession GSE67089.

KW - Glioblastoma

KW - Microarray

KW - Normalization

KW - The Cancer Genome Atlas Project

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