Abstract 4904: Activation of aldehyde dehydrogenase is essential for growth of mesenchymal glioma stem cells.

Abstract

Abstract Emerging evidence has indicated glioma stem cells(GSCs) could be subclassified into two major entities termed as as proneural(PN) GSCs and mesenchymal(MES) GSCs according to their mutually-exclusive gene expression pattern. In this study, we characterize 20 patient-derived GSCs into PN GSCs and MES GSCs based on the unbiased analysis with transcriptome microarray and microRNA profiles. Signaling pathway analysis identified the upregulation of various tumor metabolic pathways in MES GSCs. In particular, the glycolytic pathway containing several aldehyde dehydrogenase (ALDH) genes was significantly enriched in MES GSCs. ALDH activity was elevated in MES GSCs, but not in MES non-GSCs or PN GSCs, and its inhibition attenuated MES GSC growth. Intriguingly, irradiation could induce PN GSC's loss of PN phenotype and a gain of MES phenotype, indicating the irradiation-induced PN-to-MES transformation. Furthermore, selective ALDH inhibitor, DEAB, can partially block irradiation-induced transformation of PN to MES GSCs. Clinically, ALDH immunoreactivity was markedly elevated in malignant gliomas in comparison to low grade gliomas or normal brain tissues. Collectively, our data suggest that two GSC subtypes harboring distinct signaling pathways represent intertumoral glioma heterogeneity, and highlight previously unidentified roles of ALDH-associated metabolic signaling in MES MGs and their GSCs. Blocking the pathways that regulate ALDH activity might providepromising therapeutic approaches for a subset of malignant gliomas with the MES signature. Citation Format: Ping Mao, Kaushal Joshi, Jian feng Li, Jakub Godlewski, Xiao kui Mo, Shi yuan Chen, Robert W. Sobol, Ichiro Nakano. Activation of aldehyde dehydrogenase is essential for growth of mesenchymal glioma stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4904. doi:10.1158/1538-7445.AM2013-4904