Loss of retinoic acid signaling drives immune escape in IDH mutant gliomas
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA723194 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14280025_1.fastq.gz | Fastqsanger.gz | |||
| SRR14280025_2.fastq.gz | Fastqsanger.gz | |||
| SRR14280026_1.fastq.gz | Fastqsanger.gz | |||
| SRR14280026_2.fastq.gz | Fastqsanger.gz | |||
| SRR14280027_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:Gliomas are immunologically cold tumors that can be broken into several categories based on either RNA expression profiles or methylation profiles, with isocitrate dehydrogenase (IDH) mutations defining a major segregration between types. IDH mutant gliomas often exhibit defects in the retinoic acid pathway. We treated mice harboring IDH mutant gliomas with all-trans retinoic acid, and found that this treatment cause reductions in tumor growth and a swith in immune profiles in the tumor microenvironment.
2024-04-19 | GSE172387 | GEO
Project description:IDH mutant cells are deficient in retinoic acid production, which impacts downstream gene expression and pathways. We looked at the effect of supplementing IDH mutant glioma cells with ATRA on gene expression and downstream pathways. We compared gene expression changes with IDH WT cells that were also treated with ATRA
2019-12-11 | GSE141789 | GEO
Project description:Gene expression changes in IDH mutant or IDH wildtype gliomas treated with All-trans Retinoic Acid
| PRJNA594739 | ENA
Project description:Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression. CTCF occupancy characterization and histone H3K27 acetylation profiling in IDH1 mutant and wild-type glioma patient specimens and culture models. ChIP-seq raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns.
2015-12-23 | E-GEOD-70991 | biostudies-arrayexpress
Project description:Intratumoral microglia and MΦ constitute up to 70% of the tumor mass of high-grade gliomas (HGG) with profound impact on hallmarks of malignancy such as angiogenesis and immunosuppression. The dynamics and functional states of intratumoral myeloid cells during tumor progression and the molecular mechanisms controlling them are poorly understood. Here we define homeostatic and antigen-presenting myeloid cellular states in experimental and human HGG by longitudinal single-cell RNA-sequencing and combined transcriptome and proteome profiling, respectively. During glioma progression, myeloid cells gradually shift from a homeostatic to a tumor-associated effector state. We show that these dynamics are under strict control by early changes in resident microglia and the tumor genotype: In gliomas with mutations in isocitrate dehydrogenase (IDH), a disease-defining driver mutation, differentiation of invaded myeloid cells was blocked resulting in an immature, immunosuppressive phenotype. In late-stage IDH-mutant gliomas, monocyte-derived MΦ drive a tolerogenic remodeling of the glioma microenvironment thus preventing T-cell response. We define the molecular mechanism responsible for blocking functional differentiation in IDH-mutant gliomas to be causally related to enhanced metabolization of tryptophan to kynurenine, an endogenous ligand of the aryl hydrocarbon receptor (AHR), leading to a time-dependent uptake of extracellular tryptophan via LAT1-CD98 by intratumoral myeloid cells. Consequently, the immunosuppressive phenotype in IDH-mutant glioma models was reversed by pharmacologic inhibition of LAT1-CD98 or AHR. Thus, we provide evidence for a tumor genotype-dependent dynamic network of resident and recruited intratumoral myeloid cells shaping the immune microenvironment of IDH-mutant HGG and identify tryptophan metabolism as a viable therapeutic target for the immunotherapy of IDH-mutant tumors.
2021-03-04 | GSE166418 | GEO
Project description:IDH and TP53 mutant gliomas are high recurrent tumor, and thus we aimed to detect malignant and recurent factors in this genetic type of gliomas
2017-09-01 | GSE94652 | GEO
Project description:Intratumoral microglia and MΦ constitute up to 70% of the tumor mass of high-grade gliomas (HGG) with profound impact on hallmarks of malignancy such as angiogenesis and immunosuppression. The dynamics and functional states of intratumoral myeloid cells during tumor progression and the molecular mechanisms controlling them are poorly understood. Here we define homeostatic and antigen-presenting myeloid cellular states in experimental and human HGG by longitudinal single-cell RNA-sequencing and combined transcriptome and proteome profiling. During glioma progression, myeloid cells gradually shift from a homeostatic to a tumor-associated effector state. We show that these dynamics are under strict control by early changes in resident microglia and the tumor genotype: In gliomas with mutations in isocitrate dehydrogenase (IDH), a disease-defining driver mutation, differentiation of invaded myeloid cells was blocked resulting in an immature, immunosuppressive phenotype. In late-stage IDH-mutant gliomas, monocyte-derived MΦ drive a tolerogenic remodeling of the glioma microenvironment thus preventing T-cell response. We define the molecular mechanism responsible for the tumor genotype-dependent education of infiltrating MΦ to be causally related to an enzymatically enhanced tryptophan catabolism via TDO2, resulting in the production of kynurenine, an endogenous ligand of the aryl hydrocarbon receptor (AHR). TDO2 activation further induces an amino acid starvation response triggering the import of exogenous tryptophan by intratumoral MΦ via LAT1-CD98. We here provide evidence that paracrine R-2-HG and tryptophan are critically involved in the differentiation and activation of monocyte-derived MΦ and that the previously observed altered amino acid metabolism in IDHmut gliomas is also responsible for shaping an immunosuppressive tumor microenvironment through maintenance of this complex metabolic axis. We further show that this regulatory metabolic network is particularly active in infiltrating MΦ because of their distinct expression profile that constitutes an immune subset-specific metabolic vulnerability. Consequently, the immunosuppressive phenotype in IDH-mutant glioma models was reversed by pharmacological inhibition of LAT1-CD98 or AHR. Thus, we provide evidence for a tumor genotype-dependent, dynamic network of resident and recruited intratumoral myeloid cells that shape the immune microenvironment of IDH-mutant HGG through pleiotropic interaction with the tumor metabolome and identify tryptophan metabolism as a viable therapeutic target for the immunotherapy of IDH-mutant tumors.
2021-03-04 | GSE166218 | GEO
Project description:Intratumoral microglia and MΦ constitute up to 70% of the tumor mass of high-grade gliomas (HGG) with profound impact on hallmarks of malignancy such as angiogenesis and immunosuppression. The dynamics and functional states of intratumoral myeloid cells during tumor progression and the molecular mechanisms controlling them are poorly understood. Here we define homeostatic and antigen-presenting myeloid cellular states in experimental and human HGG by longitudinal single-cell RNA-sequencing and combined transcriptome and proteome profiling. During glioma progression, myeloid cells gradually shift from a homeostatic to a tumor-associated effector state. We show that these dynamics are under strict control by early changes in resident microglia and the tumor genotype: In gliomas with mutations in isocitrate dehydrogenase (IDH), a disease-defining driver mutation, differentiation of invaded myeloid cells was blocked resulting in an immature, immunosuppressive phenotype. In late-stage IDH-mutant gliomas, monocyte-derived MΦ drive a tolerogenic remodeling of the glioma microenvironment thus preventing T-cell response. We define the molecular mechanism responsible for the tumor genotype-dependent education of infiltrating MΦ to be causally related to an enzymatically enhanced tryptophan catabolism via TDO2, resulting in the production of kynurenine, an endogenous ligand of the aryl hydrocarbon receptor (AHR). TDO2 activation further induces an amino acid starvation response triggering the import of exogenous tryptophan by intratumoral MΦ via LAT1-CD98. We here provide evidence that paracrine R-2-HG and tryptophan are critically involved in the differentiation and activation of monocyte-derived MΦ and that the previously observed altered amino acid metabolism in IDHmut gliomas is also responsible for shaping an immunosuppressive tumor microenvironment through maintenance of this complex metabolic axis. We further show that this regulatory metabolic network is particularly active in infiltrating MΦ because of their distinct expression profile that constitutes an immune subset-specific metabolic vulnerability. Consequently, the immunosuppressive phenotype in IDH-mutant glioma models was reversed by pharmacological inhibition of LAT1-CD98 or AHR. Thus, we provide evidence for a tumor genotype-dependent, dynamic network of resident and recruited intratumoral myeloid cells that shape the immune microenvironment of IDH-mutant HGG through pleiotropic interaction with the tumor metabolome and identify tryptophan metabolism as a viable therapeutic target for the immunotherapy of IDH-mutant tumors.
2021-03-04 | GSE166521 | GEO
Project description:Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.
2015-12-23 | GSE70991 | GEO
Project description:All-Trans-Retinoic Acid Treatment of IDH Mutant Astrocytes
| PRJNA721930 | ENA