Abstract 3877: Evolution of cancer stem cells in glioma to promote their therapy-resistant phenotype

Abstract

Abstract High grade glioma (HGG) is a life-threatening brain tumor. Among heterogeneous tumor cells, glioma stem cells (GSCs) are defined as a subpopulation resistant to chemo- and radiotherapy with prominent tumorigenic ability. Identification of novel therapeutics designed to target the GSC population in HGGs is a challenge. The recent genome-wide transcriptome analysis identified 3 subtypes, proneural (PN), proliferative, and mesenchymal (MES), in HGGs. These HGG subtypes harbor distinct gene signatures and altered signaling pathways with some clinical relevance. During malignant transformation, HGGs appear to gain therapy resistance, at least in part, through their phenotypic drift into mesenchymal tumors. In addition, some of the current therapies, if not all, appear to induce mesenchymal transformation of HGGs resulting in more therapy-resistant tumors. Nonetheless, identification of subtype-specific GSCs remains elusive. My lab recently identified clinical HGG sample-derived two mutually-exclusive GSCs: PN and MES GSCs with striking phenotypic differences with clinical relevance (Mao et al., PNAS 2013). Transcritpome microarray analysis, miRNA profiling, and subsequent functional analysis demonstrated that distinct signaling pathways regulate tumorigenesis and propagation of the individual GSC subtypes. For example, PN GSCs are dependent on the oncogenic transcription factor c-Myb (Miyazaki et al., Clinical Cancer Res. 2012) and MES GSCs are dependent on the oncogene/mitotic kinase MELK and Survivin (Guvenc et al., Clinical Cancer Res. 2012; Gu et al., Stem Cells 2013; Joshi et al., Stem Cells 2013). Intriguingly, upon radiation treatment, PN GSCs gain the phenotypes of MES GSCs (PN-to-MES transformation; PMT), which are much more aggressive and radioresistant than original PN GSCs. Of note, targeting the MES-specific pathways partially blocks PMT of GSCs. These results may patially explain the molecular mechanisms underlying mesenchymal transformation of HGGs to promote therapy resistance. Here I summarize our latest data to elucidate the molecular mechanisms that drive GSC evolution to promote their therapy resistant phenotype. Citation Format: Ichiro Nakano. Evolution of cancer stem cells in glioma to promote their therapy-resistant phenotype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3877. doi:10.1158/1538-7445.AM2014-3877