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 down-regulated 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.
authors: Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA.
authors: Ping
authors: P
authors: Mao
authors: Kaushal
authors: K
authors: Joshi
authors: Jianfeng
authors: J
authors: Li
authors: Sung-Hak
authors: SH
authors: Kim
authors: Peipei
authors: P
authors: Li
authors: Lucas
authors: L
authors: Santana-Santos
authors: Soumya
authors: S
authors: Luthra
authors: Uma R
authors: UR
authors: Chandran
authors: Panayiotis V
authors: PV
authors: Benos
authors: Luke
authors: L
authors: Smith
authors: Maode
authors: M
authors: Wang
authors: Bo
authors: B
authors: Hu
authors: Shi-Yuan
authors: SY
authors: Cheng
authors: Robert W
authors: RW
authors: Sobol
authors: Ichiro
authors: I
authors: Nakano
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D000445:Aldehyde Oxidoreductases; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005910:Glioma / Q000201:enzymology* / Q000473:pathology; D006019:Glycolysis; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D009363:Neoplasm Proteins; D000445:Aldehyde Oxidoreductases; D000444:Aldehyde Dehydrogenase; C018699:aldehyde dehydrogenase (NAD(P)+)
keywords: cancer stem cell; epithelial-to-mesenchymal transition; glioblastoma; glioblastoma multiforme; proneural-to-mesenchymal transition
references: Nat Cell Biol. 2012 Nov;14(11):1212-22
references: 23086238
references: Cancer Cell. 2010 Jan 19;17(1):98-110
references: 20129251
references: Cancer Cell. 2012 Jul 10;22(1):21-35
references: 22789536
references: Cancer Res. 2010 Mar 1;70(5):2030-40
references: 20145155
references: Cell Cycle. 2011 May 1;10(9):1378-84
references: 21552008
references: J Clin Oncol. 2011 Jan 10;29(2):142-8
references: 21135282
references: Nature. 2004 Nov 18;432(7015):396-401
references: 15549107
references: Clin Cancer Res. 2013 Feb 1;19(3):631-42
references: 23251006
references: Cancer Res. 2009 Oct 15;69(20):8208-15
references: 19808966
references: J Neurosurg. 2011 Mar;114(3):648; discussion 648-50
references: 21054138
references: Genes Dev. 2012 Apr 15;26(8):756-84
references: 22508724
references: Cancer Res. 2009 Apr 15;69(8):3382-9
references: 19336570
references: Nature. 2006 Dec 7;444(7120):756-60
references: 17051156
references: Oncogene. 2008 May 1;27(20):2897-909
references: 18037961
references: Stem Cells. 2011 Jan;29(1):32-45
references: 21280157
references: Nature. 2010 Jan 21;463(7279):318-25
references: 20032975
references: J Exp Med. 2011 Feb 14;208(2):313-26
references: 21242296
references: Expert Opin Investig Drugs. 2009 Aug;18(8):1061-83
references: 19555299
references: Nucl Med Biol. 2008 Feb;35(2):171-6
references: 18312826
references: Cancer Cell. 2012 Oct 16;22(4):425-37
references: 23079654
references: Clin Cancer Res. 2012 Mar 1;18(5):1268-80
references: 22230766
references: Cancer Res. 2012 Aug 1;72(15):3828-38
references: 22617325
references: Neurochem Res. 2012 Jun;37(6):1192-200
references: 22228201
references: Cancer Cell. 2006 Mar;9(3):157-73
references: 16530701