Abstract 3314: Phenotypic plasticity in glioma stem cells mediated by NFκB signaling

Abstract

Abstract Here we report the identification of two major subtypes of glioma stem cells (GSCs) that closely mirror previously described glioblastoma (GBM) groups, namely proneural (PN) and mesenchymal (MES), based on gene expression patterns. Using flow cytometry, we found that PN GSCs express both CD15/SSEA1, a marker for neural stem cells, as well as CD44, a MES marker. In contrast MES GSCs were CD15low/CD44high. MES GSCs and CD44high subpopulations in PN GSCs showed increased expression of transcription factors previously reported to induce the MES phenotype (STAT3, C/EBP-α, and TAZ), and were -resistant to α-irradiation. By distilling cytokines that can induce MES differentiation, we found that TNF-α found in patient-derived microglial conditioned media or conditioned media from MES GSCs caused a PN-to-MES transition through activation of NFκB resulting in radio-resistance. We found that NFκB mediates MES transition indirectly by inducing the transcriptional circuitry of STAT3, C/EBP-α, and TAZ. Blockade of NFκB activation using minocycline abrogated the MES phenotype (both induced and constitutive), reduced tumor growth, and rendered GSCs radio-sensitive. Taken together, our findings reveal that phenotypic and surface marker plasticity is common in GSCs, and that the NFκB driven PN-to-MES transition provides an escape mechanism for GSCs to evade cytotoxic treatment. Based on our studies, we propose that minocycline, a commonly used antibiotic, could target GSCs and should be further evaluated in preclinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3314. doi:1538-7445.AM2012-3314