MiRNA expression profile of Idh1 wild-type and mutant glioma initiating cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA490168 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7814720.fastq.gz | Fastqsanger.gz | |||
| SRR7814721.fastq.gz | Fastqsanger.gz | |||
| SRR7814722.fastq.gz | Fastqsanger.gz | |||
| SRR7814723.fastq.gz | Fastqsanger.gz | |||
| SRR7814719.fastq.gz | Fastqsanger.gz |
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Project description:Human astrocytomas and oligodendrogliomas are defined by mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) 1 or 2. Mutant IDH1 causes the production and accumulation of the metabolite 2 hydroxyglutarate, which induces genome-wide hypermethylation, and is thought to be a driver mutation of these tumours. However, there are multiple contradictory effects of mutant IDH1 in cell lines and in vivo models, prompting us to study the effect of mutant IDH1 on cell differentiation, proliferation, and apoptosis. Here we established mouse glioma initiating cells (GIC) by inactivating the tumour suppressor genes Pten and p53 in the neural stem/progenitor cell population of the forebrain, and compared these GIC with triple mutant tumours expressing in addition the Idh1 R132H mutation. We found that Idh1 mutant cells proliferate less in vitro and mice with Idh1 mutant tumour survived significantly longer than their Idh1 wild type counterparts. By comparing the miRNA expression profiles of Idh wild-type and Idh mutant cells and tumours we identified miR-183-5p as a differentially expressed miRNA.
2019-08-22 | GSE119740 | GEO
Project description:Human astrocytomas and oligodendrogliomas are defined by mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) 1 or 2. Mutant IDH1 causes the production and accumulation of the metabolite 2 hydroxyglutarate, which induces genome-wide hypermethylation, and is thought to be a driver mutation of these tumours. However, there are multiple contradictory effects of mutant IDH1 in cell lines and in vivo models, prompting us to study the effect of mutant IDH1 on cell differentiation, proliferation, and apoptosis. Here we established mouse glioma initiating cells (GIC) by inactivating the tumour suppressor genes Pten and p53 in the neural stem/progenitor cell population of the forebrain, and compared these GIC with triple mutant tumours expressing in addition the Idh1 R132H mutation. We found that Idh1 mutant cells proliferate less in vitro and mice with Idh1 mutant tumour survived significantly longer than their Idh1 wild type counterparts. By comparing the RNA expression profiles of Idh wild-type and Idh mutant cells and tumours we identified endoplasmic reticulum stress pathways were significantly associated with Idh1 mutation.
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Project description:Gene expression profile of Idh1 wild-type and mutant glioma initiating cells
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Project description:Pilot study aimed at comparing miRNA profiles of human glioma cells with and without the R132H IDH1 mutation.
2016-04-30 | GSE80821 | GEO
Project description:Understanding the glioma stem cell (GSC) heterogeneity within IDH1 and TP53 mutant tumors may elucidate possible targets for astrocytoma treatment. We performed single-nucleus transcriptomics of 6 mutant and wild-type glioma samples sorted for Sox2 stem cell marker. Malignant states of different clusters were evaluated by the expression of the normal and hematopoietic markers. We found that mutant GSCs were characterized by collagen synthesis and CD44-high phenotype prone to migration, while wild-type GSCs had vulnerability points in ATP synthesis. Additionally, mutant GSCs displayed altered lipogenesis probably attributed to the low NADPH consumed by mutant IDH1. The collagen and lipid biosynthesis represent possible target pathways for prospective tackling GSCs with IDH1 R132H and TP53 point mutations, uncouplers of oxidative phosphorylation are promising to address wild-type GSC proliferation
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Project description:Mutant IDH1 promotes glioma formation in vivo
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Project description:The R132H mutation in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is the most important prognostic factor for survival of glioma patients. This resulted in many studies investigating the effects of this mutation, including those on energy metabolism. This led to the discovery of a panel of enzymes mainly involved in glutamate anaplerosis and aerobic glycolysis that change in abundance as a result of the IDH1 mutation. To further study these changes and investigate the therapeutic value of inhibitors of IDH1 R132H-associated metabolic pathways, appropriate glioma models are required that mimic in vivo metabolism as good as possible. To investigate how metabolism is affected by in vitro cell culture, we here compared surgically obtained snap frozen glioma tissues with their corresponding primary glioma cell culture models with a previously developed targeted mass spectrometry proteomic assay. We determined the relative abundance of a panel of metabolic enzymes. Results confirmed increased glutamate use and decreased aerobic glycolysis in resected IDH1 R132H glioma tissue samples. However, these metabolic profiles were not reflected in the paired glioma culture samples. Analysis of orthotopic glioma xenograft samples with and without the IDH1 mutation revealed metabolic profiles that more closely resembled clinical counterparts. We suggest that culture conditions and tumor microenvironment play a crucial role in maintaining the in vivo metabolic situation in cell culture models. For this reason, new models that more closely resemble the in vivo microenvironment, such as 3-dimensional cell co-cultures or organotypic multicellular spheroid models, need to be developed and investigated.
2022-02-14 | PXD024009 | Pride
Project description:The R132H mutation in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is the most important prognostic factor for survival of glioma patients. This resulted in many studies investigating the effects of this mutation, including those on energy metabolism. This led to the discovery of a panel of enzymes mainly involved in glutamate anaplerosis and aerobic glycolysis that change in abundance as a result of the IDH1 mutation. To further study these changes and investigate the therapeutic value of inhibitors of IDH1 R132H-associated metabolic pathways, appropriate glioma models are required that mimic in vivo metabolism as good as possible. To investigate how metabolism is affected by in vitro cell culture, we here compared surgically obtained snap frozen glioma tissues with their corresponding primary glioma cell culture models with a previously developed targeted mass spectrometry proteomic assay. We determined the relative abundance of a panel of metabolic enzymes. Results confirmed increased glutamate use and decreased aerobic glycolysis in resected IDH1 R132H glioma tissue samples. However, these metabolic profiles were not reflected in the paired glioma culture samples. Analysis of orthotopic glioma xenograft samples with and without the IDH1 mutation revealed metabolic profiles that more closely resembled clinical counterparts. We suggest that culture conditions and tumor microenvironment play a crucial role in maintaining the in vivo metabolic situation in cell culture models. For this reason, new models that more closely resemble the in vivo microenvironment, such as 3-dimensional cell co-cultures or organotypic multicellular spheroid models, need to be developed and investigated.
2022-02-16 | PXD024019 | Pride
Project description:To identify a novel miRNA that is aberrantly expressed in GICs, we analyzed differences in miRNA expression between the mouse GICs, NSCL61 and OPCL61, showing characteristic features of cancer stem cell, and their parental cells by miRNA microarrays. neural stem cells, glioma-initiating cells (GICs) from neural stem cells, oligodendrocyte precursor cells, glioma-initiating cells (GICs) from oligodendrocyte precursor cells.
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Project description:The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1) which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen dose-dependently blocked the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9M3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant - but not IDH1-wildtype – glioma cells without appreciable changes in genome wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects. Xenograft experiments were carried out with treatment cohorts of vehicle, 150mg/kg/day, 450mg/kg/day. After the indicated tumors were harvested and genomic DNA was extracted and analyzed by the Illumina 450k Methylation array.
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