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.
N1 - Funding Information:
We thank Drs. H. Kornblum (University of California at Los Angeles) and K. Palanichamy (Ohio State University) for sharing their tumor samples for this study. This work was supported by the National Institutes of Health (NIH) Grants CA148629 , GM087798 , ES019498 , and GM099213 (to R.W.S.), CA135013 (to I.N.), LM009657 (to P.V.B.), UL1RR024153 (Reis, Clinical and Translational Science Institute University of Pittsburgh), CA130966 and CA158911 (to S.-Y.C. and B.H.) and P30 CA047904 for the University of Pittsburgh Cancer Institute Core Facility (the Lentiviral Facility and the Cancer Biomarkers Facility, to R.W.S.); a Brain Cancer Research award from the James S. McDonnell Foundation (to B.H.); a Zell Scholar award from the Zell Family Foundation; funds from Northwestern Brain Tumor Institute and Department of Neurology Northwestern University (to S.-Y.C.); and the Basic Science Research Program through National Research Foundation of Korea (NRF) Grant 2011-0024089 (to S.-H.K.). P.M. was supported by the China Scholarship Council. This project also used the UPCI Cancer Bioinformatics Services which is supported in part by the National Cancer Institute award P30CA047904 .
Publisher Copyright:
© 2015 .
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
UR - http://www.scopus.com/inward/record.url?scp=84937207618&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937207618&partnerID=8YFLogxK
U2 - 10.1016/j.gdata.2015.07.007
DO - 10.1016/j.gdata.2015.07.007
M3 - Article
C2 - 26251826
AN - SCOPUS:84937207618
VL - 5
SP - 333
EP - 336
JO - Genomics Data
JF - Genomics Data
SN - 2213-5960
ER -
