Genotying of human glioma cell lines reveals epigenetic-mediated dysfunction of the bmp pathway inhibits differentiation of human glioblastoma initiating cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Howard Fine
PROVIDER: E-GEOD-10007 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Despite similarities between tumor initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues, and by converting otherwise cytostatic signals to pro-proliferative signals. Keywords: Genomic alterations
2008-01-07 | GSE10007 | GEO
Project description:The aim of this study is to determine if, using antioxidant drugs, it is possible to interfere with the proliferative capabilities of the human glioblastoma (GBM) tumor-initiating cells (TICs). To establish which cellular processes are activated in GBM TICs by the antioxidants NAC, Tiron and Trolox, we generated and analyzed the gene expression profiles after treatment with these compounds and with H2O and EtOH (vehicles).
2014-03-04 | E-GEOD-44099 | biostudies-arrayexpress
Project description:Most patients affected by Glioblastoma multiforme (GBM) experience a recurrence of the disease because of the spreading of tumor-initiating cells (TICs) beyond surgical boundary. Unveiling and targeting molecular mechanisms causing this process is a logic goal to impair GBM killing ability. In an orthotopic xenograph model, we have noticed that GBM TICs isolated from several patients may fall into two classes of invasive behavior: nodular or diffuse. In order to identify genes responsible for the diffusive type of invasion, we have compared by genome expression analysis, cultured GBM TICs belonging to the two classes. This analysis allowed us to identify a small group of regulated genes in the diffusive type of GBM TICs. The gene ontology process of cell adhesion and the localization of the gene product functions to the plasmamembrane resulted significantly associated to this gene set. Real time RT-PCR and immunofluorescence analyses performed for a selected subgroup of regulated genes/gene products confirmed the results obtained by the expression analysis. Some of the genes that we found upregulated in our screening were already proven to be involved in Glioma cell invasion supporting our study. However, we have also identified genes that were not previously implicated in this process. To assess whether these are required to sustain TICs GBM invasion, we silenced a subset of them and evaluated in Boyden chamber the invasive ability of the cells. Our study provides novel target genes to be evaluated for the inhibition of GBM diffusion within the SNC. As we observed that GBM TICs may fall into two classes of M-bM-^@M-^\in vivoM-bM-^@M-^] invasive behavior in mouse orthotopic transplantation: expansive or highly diffusive, resulting in the hostM-bM-^@M-^Ys white and gray matters substitution, we decided to identify genes associated with the latter phenotype by microarray analysis. Three replicates of each class were analyzed.
2012-09-11 | E-GEOD-16805 | biostudies-arrayexpress
Project description:Glioblastomas (GBM) are poorly differentiated astrocytic tumors arising in the Central Nervous System (CNS), which despite aggressive treatments are still characterized by a fatal outcome. Several studies have shown the existence of a subpopulation of cells within glioma tumors displaying cancer stem cells properties. As the term âtumor initiating cellsâ (TICs) is frequentely used to describe cells as these with cancer stem cells capacity. Because TICs promotes the tumor chemo- and radio-resistance and angiogenesis it is conceivable that finding a mean to kill these cells would lead to a better therapy for GBM. The NOTCH gene has an important role during the CNS development, in the maintenance of dividing cells in promoting neural lineage entry of Embryonic Stem Cells and the differentiation of astroglia from the rat adult hippocampus-derived multipotent progenitors. The activation of the NOTCH signaling requires the proteolytic processing of this type I integral membrane protein by a two step process catalyzed first by a metalloprotease and then by the gamma-secretase. An increased activation of the NOTCH signaling has been implicated in several tumors types. Recently some studies showed that this pathway induces the survival/proliferation in GBM and glioma cells, and the expression of stem cell properties in glioma cells. Accordingly to these findings, the inhibition of this pathway leads to depletion of stem-like cells and blocks the engraftment in embryonal brain tumors. Furthermore, enhanced NOTCH signaling may lead to one of the tumor resistance mechanisms deployed by GBM. Targeting the NOTCH pathway specifically in GBM TICs appears therefore as a rational approach for exploring novel and hopefully more effective therapeutic strategies for the management of this malignancy. Several molecular tools are available for targeting the Notch pathway such as specific siRNAs, shRNAs or drugs such as gamma-secretase inhibitors. Among these tools, the latter are small peptides/molecules able to inhibit the gamma-secretase by distinct mechanisms. In this study we used two drugs known as gamma-secretase inhibitors, to investigate by gene expression profiling, their ability to interfere specifically with the proliferative properties of GBM TICs previously obtained in our laboratory. Our data show that one of these two drugs, LLNle, is effective in killing these cells in vitro by activating protein catabolic process mediated by the proteasome, suggesting that preclinical studies should definitely be carried on to evaluate whether LLNle is able to significantly improve the survival in hybrid human GBM-animal models. Gamma-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. In this study we employed two of such inhibitors, namely the z-Leu-leu-Nle-CHO (LLNle) and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to verify whether they were effective in vitro in the killing of human GBM tumor initiating cells (TICs). We first established that of the two drugs only LLNle reduces the viability of GBM TICs obtained from three different patients in the low micromolar range. Cells were treated with 7.5 μM LLNle or DAPT or vehicle alone (DMSO 0.1%) and kept in a humidified 5% CO2 atmosphere at 37°C for the indicated time period (24 or 48 hours). To establish which cellular processes are activated in GBM TICs by LLNle we generated and analyzed the gene expression profile after treatment with this compound and with DAPT and DMSO (vehicle). Our data show that LLNle induces upregulation of genes coding for proteasome subunits and subsequently mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activation of genes acting as mitotic inhibitors. Our data are consistent with proteasome inhibition by LLNle, subsequent upregulation of proteasome activity and subsequent unleash of the apoptotic process in GBM TICs.
2010-04-09 | E-GEOD-14581 | biostudies-arrayexpress
Project description:Demethyl fructiculin A is a diterpenoid quinone component of the exudates from Salvia corrugata (SCO-1) leafes. SCO-1 was recently reported to induce anoikis in mammalian cell lines via a molecular mechanism involving the presence of the membrane scavenging receptor CD36. However, experiments performed with cells lacking CD36, showed that SCO-1 was able to induce apoptosis also via alternate pathways. To contribute to a better characterization of the molecular mechanisms underlining the cytotoxic activity of SCO-1, we decided to pursue an unbiased pharmacogenomic approach by generating the gene expression profile of GBM TICs subjected to the administration of SCO-1 and comparing it with that of control cells exposed to the solvent. With this strategy we hypothesized to highlight those pathways and biological processes unlashed by SCO-1. Using this approach we unveiled that the main mechanism responsible for the SCO-1 pro-apoptotic effect is superoxide generation in mitochondria and that this molecule has potential chemotherapeutic properties that should be further investigated in GBM xenotransplant models. To get an insight on the biological processes and pathways elicited by Demethyl fructiculin A (SCO-1), we undertake an unbiased genomic approach in order to identify genes deregulated by SCO-1. Cells were treated with 9.3 μg/ml concentration (IC50 at 48h) or vehicle alone (DMSO) and kept in a humidified 5% CO2 atmosphere at 37°C for the indicated time period (24 or 48 hours). After 24 hours of exposure of glioblastoma tumor initiating cells (GBM TICs) to SCO-1, we found the deregulation of genes belonging to the Glutathione metabolism pathway and of those belonging to the biological processes related to the response to stress and chemical stimulus.
2010-10-15 | E-GEOD-19846 | biostudies-arrayexpress
Project description:Stem cell markers such as NANOG have been implicated in various cancers; however, the functional contribution of NANOG to cancer pathogenesis has remained unclear. In the present study, we show that Toll-like receptor 4 (TLR4) signaling phosphorylates E2F1 to transactivate NANOG. Down-regulation of Nanog significantly reduces tumor development. In the search for the NANOG-dependent mechanisms underlying growth of tumor-initiating stem-like cells (TICs), NANOG ChIP-seq identifies the genes associated with mitochondrial metabolic pathways. Genome wide Identification of Nanog binding partners in tumor initating stem cells
2016-01-07 | E-GEOD-68237 | biostudies-arrayexpress
Project description:Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor. The brain-infiltrative character of glioblastoma makes complete surgical removal of the tumor impossible and neither radiation nor current chemotherapy provide cure. Recent evidence shows that glioblastoma multiforme consists of heterogeneous cell populations which differ in tumor-forming potential. Enriched tumor-initiating capacity has been linked to poorly differentiated glioblastoma cells sharing features with neural stem cells. Thus, these cells are important targets for new therapeutic strategies. We aim to identify novel targets controlling maintenance and differentiation in glioblastoma-initiating cells through high throughput screening. To this end, we utilized libraries of small chemical compounds and small interference RNAs in combination with automated imaging and data analysis. Patient-derived glioblastoma cells were expanded and characterized using neural stem cell conditions. In culture, the cells showed low differentiation but expression of neural stem cell markers such as Nestin and Sox2. Upon intracranial injection into SCID mice these cells gave rise to tumors displaying the hallmarks of the human disease. Differentiation of glioblastoma-initiating cells (for example elicited through bone morphogenetic protein, BMP) was associated with strong morphological changes. Hence, cellular morphology, as well as markers specific for differentiation or death were used as screen readout. Lentiviral RNA interference-based screening yielded several gene knockdowns leading to ‘forced’ differentiation of glioblastoma-initiating cells. For example, knockdown of TRRAP (transformation/transcription domain associated protein) led to strongly increased differentiation and loss of proliferative and self-renewing capacity in these cells. TRRAP is an adapter protein implicated in oncogenic transformation through c-MYC transcription activation, also participating in chromatin remodeling and DNA repair. Glioblastoma-initiating cells with reduced TRRAP displayed increased apoptosis upon treatment with the genotoxic agent temozolomide. In vivo, Trapp knockdown cells were not able to give rise to glioblastoma upon transplantation into the brain of SCID mice. Together, these findings support a crucial role for TRRAP in maintenance and tumorigenicity of glioblastoma-initiating cells and might offer future therapeutic options. Two treatments compared to control: two different shRNA sequences for TRRAP were compared to a control shRNA sequence in their effects on global transcription in brain tumor initiating cells
2011-03-14 | E-GEOD-27931 | biostudies-arrayexpress
Project description:Oligodendrocyte development is tightly controlled by extrinsic signals; however, mechanisms that modulate cellular responses to these factors remain unclear. Six-transmembrane glycerophosphodiester phosphodiesterases (GDEs) are emerging as central regulators of cellular differentiation via their ability to shed glycosylphosphatidylinositol (GPI)-anchored proteins from the cell surface. We show here that GDE3 controls the pace of oligodendrocyte generation by negatively regulating oligodendrocyte precursor cell (OPC) proliferation. GDE3 inhibits OPC proliferation by stimulating ciliary neurotrophic factor (CNTF)-mediated signaling through release of CNTFRα, the ligand-binding component of the CNTF-receptor multiprotein complex, which can function as a soluble factor to activate CNTF signaling. GDE3 releases soluble CNTFRα by GPI-anchor cleavage from the plasma membrane and from extracellular vesicles (EVs) after co-recruitment of CNTFRα in EVs. These studies uncover new physiological roles for GDE3 in gliogenesis and identify GDE3 as a key regulator of CNTF-dependent regulation of OPC proliferation through release of CNTFRα.
2019-09-06 | GSE135819 | GEO
Project description:Chromatin accessibility was profiled by ATAC-seq in normal and glioblastoma-derived neural stem (GNS) cells, in self-renewing conditions and in response to differentiation stimulus with bone morphogenic protein (BMP).
2015-10-01 | E-MTAB-3868 | biostudies-arrayexpress
Project description:The transcriptional response of normal and glioblastoma-derived neural (GNS) cells was profiled in self-renewing conditions and over a time course of differentiation in the presence of bone morphogenic protein (BMP).
2015-10-02 | E-MTAB-3867 | biostudies-arrayexpress