Abstract LB-114: Molecular and lineage analysis of glioblastoma stem cells identifies clinically relevant models of glioblatoma

Abstract

Abstract The Cancer Genome Atlas project described a robust gene expression-based molecular classification of GBM. However, the functional and biological significance of the molecular subclasses are being determined. In this study, we hypothesize that Glioma Stem Cells (GSCs) isolated from individual patient tumor samples will recapitulate the molecular characteristics of tumor samples and provide a relevant model for functional analysis of the molecular subclasses. Thus we conducted a comprehensive analysis of 26 GSC lines with expression array, RPPA, and a series of neural lineage markers. Analysis of the expression data classified the 26 GSC lines into four subtypes (Classical, Proneural 1, Proneural 2 and Mesenchymal,) closely similar to the TCGA subclasses with a distinct profile for each subtype (c-Myc, Cyclin D2 for Classical; Olig2, NKX2–2, Notch-1, Notch-3 for Proneural 2; BMP4, DCX, p16INK4a, ID2 for Proneural 1; CD44, CAV1, TGFBR2 for Mesenchymal). Further analysis showed that GSC subtypes exhibit divergent patterns of signaling pathway activation. The major pathways activated in 4 subtypes were Notch pathway in Proneural 2, Wnt/β-Catenin in Proneural 2 and Classical, while FGF/VEGF and TGF-β in Mesenchymal. In vitro treatment with SB 431542, a TGF-βR inhibitor, showed that Mesenchymal subtype is more sensitive than other subtypes. More importantly, lineage analysis of GSCs subtypes show that Proneural and Classical GSCs differentially express lineage markers for neural stem/progenitor cells and were responsive to differentiating agent retinoic acid. In addition, GSC subtypes exhibit distinct biological behaviors in self-renewal capacity, proliferation, invasiveness, angiogenic potential, response to growth factor stimulus, and differentiation in vitro and in vivo with Classical subtype being more proliferative and Mesenchymal subtype being more angiogenic and invasive. In conclusion, our comprehensive analysis showed that GSCs reflect patient tumor subclass and these subtypes showed distinct regulatory pathway activation, lineage profile and biological behaviors. Thus GSC is biologically and molecularly a more relevant model system for preclinical studies of therapeutic intervention and to expand our molecular understanding of human GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-114. doi:10.1158/1538-7445.AM2011-LB-114