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Analysis of Sox2-regulated transcriptome in glioma stem cells

ABSTRACT: Glioblastoma is the most malignant brain tumor in adults and is associated with poor survival despite multimodal treatments. Glioma stem cells (GSCs) are cells with properties reminiscent from the normal neural stem cells counterparts. They have been postulated to be the culprit of glioma chemo- and radio-resistance ultimately leading to relapse. Understanding the molecular circuits governing the GSC compartment is essential. Sox2, a critical transcription regulator of embryonic and neural stem cell function, is deregulated in GSCs, but the description of the precise molecular pathways regulated by this gene in GSCs remains poorly understood. Results: We performed a genome-wide analysis of Sox2-regulated transcripts in GSCs, using microarray. We identified a total of 135 differentially expressed coding transcripts and 261 non-coding transcripts (B value > 0). Cell adhesion and cell-cell signaling are among the most enriched terms using GO classification. The pathways altered after Sox2 down-modulation includes multiple cellular processes such as aminoacid metabolism and intercellular signaling cascades. We validate the top 5 down regulated coding genes and one of the top 5 up-regulated coding genes. We also defined and classify the set of non-coding transcripts differentially expressed regulated by Sox2 in GSCs, and validated two of them. Conclusions: We present a comprehensive analysis of the transcriptome controlled by Sox2 in GSCs, gaining insights in the understanding of the potential roles of Sox2 in glioblastoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79302 | GEO | 2016/11/04

SECONDARY ACCESSION(S): PRJNA315430

REPOSITORIES: GEO

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Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma

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2021-11-04 | PXD028933 | Pride

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Project description:Glioblastoma stem cells (GSCs) fate is controlled by environmental cues, among which cytokines play a crucial role. The transforming growth factor β (TGFβ) family signaling pathways controls GSCs. On one hand, TGFβ promotes cell proliferation in GBM, it induces the expression of platelet-derived growth factor-B (PDGFB). Moreover, TGFβ, via its signaling mediators Smad2/3, induces the expression of the cytokine leukemia inhibitory factor (LIF) and Sox4, which in turn enhances the expression of the stem cell transcription factor Sox2; this increases the self-renewal capacity of the GSCs and their stemness characteristics, and enhances the GSC tumor-initiating potential. On the other hand, Bone morphogenic proteins (BMPs) are known to promote GSC differentiation towards the astrocytic phenotype. To further understand which genes are regulated by TGFβ and BMP7 in GSCs we performed a microarray in the Affymetrix HTA2 platform in three different glioblastoma cell line, U2987, and two patient-derived glioblastoma stem cells, U3031MG and U3034MG, in the presence or absence of 5 ng/ml of TGFβ or 30 ng/ml BMP7 for 24 h, three biological replicates per condition.

2020-09-01 | E-MTAB-9076 | biostudies-arrayexpress

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Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma [scRNA-seq]

2022-10-24 | GSE184696 | GEO

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2018-01-10 | PXD006069 | Pride

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2022-01-01 | E-MTAB-9607 | biostudies-arrayexpress

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2023-04-06 | PXD030092 | Pride

A Proneural to Mesenchymal Transition Mediated by NFkB Promotes Radiation Resistance in Glioblastoma (part 1)

Project description:SUMMARY Despite numerous genome-wide association studies involving glioblastoma (GBM), few therapeutic targets have been identified for this disease. Using patient derived glioma sphere cultures (GSCs), we have found that a subset of the proneural (PN) GSCs undergo transition to a mesenchymal (MES) state in a TNFa/NFkB dependent manner with an associated enrichment of CD44 sub-populations and radio-resistant phenotypes. To the contrary, MES GSCs exhibit constitutive NFkB activation, CD44 enrichment and radio-resistance. Patients whose tumors exhibit a higher MES metagene, increased expression of CD44, or activated NFkB were associated with poor radiation response and shorter survival. Our results indicate that NFkB activation mediated MES differentiation and radiation resistance presents an attractive therapeutic target for GBM. SIGNIFICANCE In this study, we show plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radio-resistance, which we implicate as NFkB- dependent. Newly diagnosed GBM samples show a direct correlation between radiation response, higher MES metagene, CD44 expression, and NFkB activation. This correlation is also observed in the subset of GBM samples that do not exhibit IDH1 mutation, a favorable prognostic marker. Our results uncover a previously unknown link between subtype plasticity that is regulated by NFkB. Inhibition of NFkB activation can directly impact radio-resistance and presents an attractive therapeutic target for GBM. Gene expression data for 17 isolated Glioma Stem Cells

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