Single-Cell Sequencing of IDH-Mutant Glioma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE270109 | GEO | 2024/06/21
REPOSITORIES: GEO
Similar Datasets
Project description:The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression, but only a limited view of a highly complex glioma associated immune contexture across isocitrate dehydrogenase mutation (IDH) classified gliomas is known. Herein, we present an unprecedentedly comprehensive view of myeloid and lymphoid cell type diversity with our m-RNA sequencing interrogation.
2024-06-23 | GSE222518 | GEO
Project description:Background: Signaling by receptor tyrosine kinases (RTK) is frequently dysregulated in gliomas. Inter-individual variability in the causes for dysregulated RTK signaling may have hampered the efficacy of targeted therapies. Using gene expression modules around key regulators in the RAS-RAF-MEK-MAPK cascade and in the phosphatidylinositol 3-kinase-AKT pathways, we developed a âRMPAâ clustering scheme to distinguish gliomas with varying extents of RTK signaling. Results: We identified gene modules consistently co-expressed with NF1 (NF1-M), Sprouty (SPRY-M) and PTEN (PTEN-M) in gliomas. Their signatures enabled robust clustering of adult diffuse gliomas of WHO grades II-IV into RMPAhigh and RMPAlow phenotypes in a morphology-independent manner. In five independent data sets from three continents containing more than 1500 adult diffuse gliomas, RMPAhigh gliomas were associated with poor prognosis while RMPAlow gliomas were not. The RMPAhigh and RMPAlow glioma subtypes showed distinct levels of the activities of RAS-RAF-MEK-MAPK cascade and PI3K-AKT pathway and harbored unique sets of genomic alterations in the RTK signaling-related genes. The RMPAhigh gliomas contained large numbers of immature vessel cells and tumor associated macrophages and both cell types expressed high levels of pro-angiogenic RTKs including MET, VEGFR1, KDR, EPHB4 and NRP1. Conclusion: Inter-glioma variability in RTK signaling activities can be defined using the RMPA clustering scheme. The combined signatures of NF1-M, SPRY-M and PTEN-M reflect RTK signaling activity both in the glioma cells and in the glioma microenvironment. Our data show that RTK signaling in the glioma microenvironment may play a pivotal role in glioma progression. Transcriptome data from 22 fresh gliomas (2 astrocytoma II, 1 oligodendrocytoma II, 7 oligoastrocytoma II, 4 anaplastic oligoastrocytoma III and 8 GBM) were obtained using Affymetrix Human Gene 1.0 ST Array. Unsupervised hierarchical clustering of the expression data for the SPRY-M, NF1-M and PTEN-M was performed on these transcriptome data to identify samples with RMPAhigh or RMPAlow signature.
2015-10-30 | E-GEOD-74462 | biostudies-arrayexpress
Project description:The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression, but only a limited view of a highly complex glioma associated immune contexture across isocitrate dehydrogenase mutation (IDH) classified gliomas is known. Herein, we present an unprecedentedly comprehensive view of myeloid and lymphoid cell type diversity with our single cell RNA sequencing interrogation.
2024-06-23 | GSE222520 | GEO
Project description:Gliomas are aggressive lethal solid brain tumors arising from support cells in the central nervous system. Despite intense efforts to optimize the treatment of gliomas, the outcomes of high grade glioma patients are still frustrating. The causes and progress of gliomas have been investigated extensively; however, the genetic factors involved in the development of this disease remain poorly understood. We used microarrays to detail the global program of gene expression in different grade glioma tissues and try to find out some genes associated with the tumorigenesis of gliomas. Grade I to grade IV glioma tissues were selected in surgical operations for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain gene expression profiles. To that end, we hand-selected several genes that were differentially expressed in different grade glioma tissues and then performed a further study to identify the role of these genes in the process of the development of gliomas.
2013-04-10 | E-GEOD-45921 | biostudies-arrayexpress
Project description:Glioblastoma (GBM) is the most frequent and most aggressive form of diffuse glioma. The prognosis is very poor, with a median overall survival of 15 months after maximum safe resection and radiochemotherapy.GBM is one of the most genetically unstable cancers. It is characterized by numerous chromosome (chr) copy number alterations (CNA), such as chr 7 gain, chr 9p loss, and chr 10 loss, along with CDKN2A homozygous deletion (chr 9p21) and EGFR amplification (chr 7p11).Chromosome instability (CIN) may be the cause or the consequence of GBM development. In high-grade diffuse gliomas (HGG), CIN may initiate tumorigenesis. To identify recurrent genomic abnormalities in IDH WT glioblastomas, SNP arrays (Illumina 850K CytoSNP) were analyzed for 123 IDH WT GBM cases.
2018-02-27 | E-MTAB-6371 | biostudies-arrayexpress
Project description:The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression, but only a limited view of a highly complex glioma associated immune contexture across isocitrate dehydrogenase mutation (IDH) classified gliomas is known. Herein, we present an unprecedentedly comprehensive view of T cells from brain TIME at single cell resolution, which served as part of our pan-cancer T cell atlas analysis.
2023-06-29 | GSE236082 | GEO
Project description:Gliomas are the most frequent type of primary tumor of the central nervous system in adults with significant morbidity and mortality. Despite the development of novel, complex, multidisciplinary, and targeted therapies, glioma therapy has not progressed much over the last decades. Therefore, there is an urgent need to develop novel patient-adjusted immunotherapies that actively stimulate antitumor T cells generating long-term memory and thus resulting in significant clinical benefits. This work aimed to investigate the efficacy and molecular mechanism of dendritic cell (DC) vaccines loaded with glioma cells undergoing immunogenic cell death (ICD) induced by photosens based photodynamic therapy (PS-PDT) and to identify reliable prognostic genes’ signatures for predicting patients’ overall survival (OS). The analysis of the transcriptional program of the ICD-based DC vaccine led to the identification of robust induction of Th17 signature when used as a vaccine, these DCs demonstrate retinoic acid receptor-related orphan receptor-γt dependent efficacy in orthotopic mouse model. Moreover, by comparative analysis of transcriptome program of the ICD-based DC vaccine with transcriptome data from the TCGA-low grade glioma (LGG) dataset the four-gene signature (CFH, GALNT3, SMC4, VAV3) associated with OS of glioma patients have been identified. This model has been validated on OS of CGGA-LGG, TCGA-glioblastoma multiforme (GBM) and CGGA-GBM datasets to determine whether it has a similar prognostic value. For this the sensitivity and specificity of the prognostic model for predicting the OS were evaluated by calculating the area under curve (AUC) of the time-dependent receiver operating characteristic (ROC) curve. The values of AUC for TCGA-LGG, CGGA-LGG, TCGA-GBM and CGGA-GBM were, respectively, 0.75, 0.73, 0.9 and 0.69 for predicting 5-year survival rates. These data open attractive prospects for improving glioma therapy by employing ICD and PS-PDT-based DC vaccines to induce Th17 immunity and to use this prognostic model to predict the OS of glioma patients.
2022-12-21 | GSE218081 | 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: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:Astrocytoma, oligodendroglioma, oligoastrocytoma, and ependymoma are the main histologic subtypes of glioma. The molecular character of these subtypes has profound implications for understanding their causes and treatment. We describe the epigenetic landscape of these tumor types using novel DNA methylation profiling tools. There is a robust association of methylation profile with tumor histology and IDH1 mutation status. Furthermore, tumors with IDH1 mutation independently predict a tumor hypermethylator phenotype, histology, TP53 mutation status, patient age, and survival. Integrating tumor epigenetic and genetic alterations, this work provides a critical step toward better defining the somatic nature of glioma which will have great potential to impact clinical approaches to disease. This work provides an important step forward in classification of malignant brain tumors using DNA methylation profiling, integrating knowledge regarding IDH1 mutation in gliomas. The epigenetic homogeneity of the IDH1 mutant subclass despite histologic diversity implies that IDH1 mutation is a “driver” or functional determinant of a distinct DNA methylation phenotype, suggesting a novel role for an altered metabolic profile in the brain. This association occurs across histologic subtypes and demonstrates a clear relationship between genetic alteration and epigenetic profile. Fresh frozen tumor tissues were obtained from the University of California San Francisco (UCSF) Brain Tumor Research Center tissue bank with appropriate institutional review board approval. Tumors were diagnosed between 1990 and 2003. Tumor samples were defined as secondary GBM if the patients had prior histological diagnosis of a low-grade glioma. Tumors had previously been reviewed by UCSF neuropathologists to assign histologic subtype and grade. Normal brain tissue samples were from cancer-free patients who underwent temporal lobe resection as treatment for epilepsy at UCSF.
2010-12-20 | E-GEOD-20395 | biostudies-arrayexpress