TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE184567 | GEO | 2022/09/21
REPOSITORIES: GEO
Similar Datasets
Project description:TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing
| PRJNA765042 | ENA
Project description:A Cartes d'Identite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net: Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished based on the IDH mutation and the 1p/19q co-deletion. Here we performed an integrated analysis of the transcriptome, genome and methylome of 156 OT. Beyond the 3 well-known molecular classes, our multi-omics classification revealed 3 subgroups within 1p/19q co-deleted tumours, associated with different expression patterns of oligodendroglial progenitor cell (OPC), astrocytic, oligodendrocytic and neuronal lineage genes. The validity of these 3 subgroups was confirmed on public datasets. The OPC-like group was associated with a more aggressive histological and genomic profile and with MYC activation that occurred through various alterations including MYC locus genomic gain, MYC exon 3 hypo-methylation and down-regulation of microRNA-34b/c. In the lower grade glioma TCGA dataset, the OPC-like group was associated with a poorer outcome independently from histological grade. Our study unravels previously unrecognized heterogeneity among 1p/19q co-deleted tumours.
2016-03-11 | E-MTAB-3901 | biostudies-arrayexpress
Project description:A Cartes d'Identite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net: Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished based on the IDH mutation and the 1p/19q co-deletion. Here we performed an integrated analysis of the transcriptome, genome and methylome of 156 OT. Beyond the 3 well-known molecular classes, our multi-omics classification revealed 3 subgroups within 1p/19q co-deleted tumours, associated with different expression patterns of oligodendroglial progenitor cell (OPC), astrocytic, oligodendrocytic and neuronal lineage genes. The validity of these 3 subgroups was confirmed on public datasets. The OPC-like group was associated with a more aggressive histological and genomic profile and with MYC activation that occurred through various alterations including MYC locus genomic gain, MYC exon 3 hypo-methylation and down-regulation of microRNA-34b/c. In the lower grade glioma TCGA dataset, the OPC-like group was associated with a poorer outcome independently from histological grade. Our study unravels previously unrecognized heterogeneity among 1p/19q co-deleted tumours.
2016-03-11 | E-MTAB-3896 | biostudies-arrayexpress
Project description:'A Cartes d''Identite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net: Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished based on the IDH mutation and the 1p/19q co-deletion. Here we performed an integrated analysis of the transcriptome, genome and methylome of 156 OT. Beyond the 3 well-known molecular classes, our multi-omics classification revealed 3 subgroups within 1p/19q co-deleted tumours, associated with different expression patterns of oligodendroglial progenitor cell (OPC), astrocytic, oligodendrocytic and neuronal lineage genes. The validity of these 3 subgroups was confirmed on public datasets. The OPC-like group was associated with a more aggressive histological and genomic profile and with MYC activation that occurred through various alterations including MYC locus genomic gain, MYC exon 3 hypo-methylation and down-regulation of microRNA-34b/c. In the lower grade glioma TCGA dataset, the OPC-like group was associated with a poorer outcome independently from histological grade. Our study unravels previously unrecognized heterogeneity among 1p/19q co-deleted tumours.'
2016-06-15 | E-MTAB-3902 | biostudies-arrayexpress
Project description:A Cartes d'Identite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net: Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished based on the IDH mutation and the 1p/19q co-deletion. Here we performed an integrated analysis of the transcriptome, genome and methylome of 156 OT. Beyond the 3 well-known molecular classes, our multi-omics classification revealed 3 subgroups within 1p/19q co-deleted tumours, associated with different expression patterns of oligodendroglial progenitor cell (OPC), astrocytic, oligodendrocytic and neuronal lineage genes. The validity of these 3 subgroups was confirmed on public datasets. The OPC-like group was associated with a more aggressive histological and genomic profile and with MYC activation that occurred through various alterations including MYC locus genomic gain, MYC exon 3 hypo-methylation and down-regulation of microRNA-34b/c. In the lower grade glioma TCGA dataset, the OPC-like group was associated with a poorer outcome independently from histological grade. Our study unravels previously unrecognized heterogeneity among 1p/19q co-deleted tumours.
2016-03-11 | E-MTAB-3907 | biostudies-arrayexpress
Project description:A Cartes d'Identite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net: Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished based on the IDH mutation and the 1p/19q co-deletion. Here we performed an integrated analysis of the transcriptome, genome and methylome of 156 OT. Beyond the 3 well-known molecular classes, our multi-omics classification revealed 3 subgroups within 1p/19q co-deleted tumours, associated with different expression patterns of oligodendroglial progenitor cell (OPC), astrocytic, oligodendrocytic and neuronal lineage genes. The validity of these 3 subgroups was confirmed on public datasets. The OPC-like group was associated with a more aggressive histological and genomic profile and with MYC activation that occurred through various alterations including MYC locus genomic gain, MYC exon 3 hypo-methylation and down-regulation of microRNA-34b/c. In the lower grade glioma TCGA dataset, the OPC-like group was associated with a poorer outcome independently from histological grade. Our study unravels previously unrecognized heterogeneity among 1p/19q co-deleted tumours.
2016-03-11 | E-MTAB-3905 | biostudies-arrayexpress
Project description:The outcome of patients with anaplastic gliomas varies considerably depending on histology and single molecular markers such as codeletion of 1p/19q and mutations of the isocitrate dehydrogenase (IDH) gene. Whether a molecularly-based classification of anaplastic gliomas based on large scale genomic or epigenomic analyses is superior to histopathology, may reflect distinct biological subtypes, predict outcome and guide therapy decisions had yet to be determined. Epigenome-wide DNA methylation analysis, which also allows for the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering demonstrated two main groups based on IDH mutation status: CpG island methylator phenotype (CIMP) positive (77.5%) or negative (22.5%). CIMP+ (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q, but not based on histopathology. CIMP- (IDH wild type) tumors on the other hand showed hallmark copy-number alterations of glioblastomas. These tumors clustered together with CIMP- glioblastomas without forming separate groups based on WHO grade. There was no Tumor classification based on CIMP and 1p/19q status was significantly associated with survival allowing a better prediction of outcome than the current histopathological classification alone: Patients with CIMP+ tumors with 1p/19q codeletion had the best prognosis, followed by patients with CIMP+ but intact 1p/19q status. Patients with CIMP- anaplastic gliomas had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped into three molecular subtypes with clear association to underlying biology and clinical outcome based on IDH and 1p/19q status. The data do not provide a molecular basis for the diagnosis of anaplastic oligoastrocytoma.
2014-06-06 | GSE58218 | GEO
Project description:The outcome of patients with anaplastic gliomas varies considerably depending on histology and single molecular markers such as codeletion of 1p/19q and mutations of the isocitrate dehydrogenase (IDH) gene. Whether a molecularly-based classification of anaplastic gliomas based on large scale genomic or epigenomic analyses is superior to histopathology, may reflect distinct biological subtypes, predict outcome and guide therapy decisions had yet to be determined. Epigenome-wide DNA methylation analysis, which also allows for the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering demonstrated two main groups based on IDH mutation status: CpG island methylator phenotype (CIMP) positive (77.5%) or negative (22.5%). CIMP+ (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q, but not based on histopathology. CIMP- (IDH wild type) tumors on the other hand showed hallmark copy-number alterations of glioblastomas. These tumors clustered together with CIMP- glioblastomas without forming separate groups based on WHO grade. There was no Tumor classification based on CIMP and 1p/19q status was significantly associated with survival allowing a better prediction of outcome than the current histopathological classification alone: Patients with CIMP+ tumors with 1p/19q codeletion had the best prognosis, followed by patients with CIMP+ but intact 1p/19q status. Patients with CIMP- anaplastic gliomas had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped into three molecular subtypes with clear association to underlying biology and clinical outcome based on IDH and 1p/19q status. The data do not provide a molecular basis for the diagnosis of anaplastic oligoastrocytoma. We investigated a subset of 228 anaplastic gliomas using the Illumina 450k methylation array.
2014-06-06 | E-GEOD-58218 | biostudies-arrayexpress
Project description:BackgroundIDH mutant gliomas are grouped into astrocytomas or oligodendrogliomas depending on the codeletion of chromosome arms 1p and 19q. Although the genomic alterations of IDH mutant gliomas have been well described, transcriptional changes unique to either tumor type have not been fully understood. Here, we identify Tripartite Motif Containing 67 (TRIM67), an E3 ubiquitin ligase with essential roles during neuronal development, as an oncogene distinctly upregulated in oligodendrogliomas.MethodsWe used several cell lines, including patient-derived oligodendroglioma tumorspheres, to knock down or overexpress TRIM67. We coupled high-throughput assays, including RNA sequencing, total lysate-mass spectrometry (MS), and coimmunoprecipitation (co-IP)-MS with functional assays including immunofluorescence (IF) staining, co-IP, and western blotting (WB) to assess the in vitro phenotype associated with TRIM67. Patient-derived oligodendroglioma tumorspheres were orthotopically implanted in mice to determine the effect of TRIM67 on tumor growth and survival.ResultsTRIM67 overexpression alters the abundance of cytoskeletal proteins and induces membrane bleb formation. TRIM67-associated blebbing was reverted with the nonmuscle class II myosin inhibitor blebbistatin and selective ROCK inhibitor fasudil. NOGO-A/Rho GTPase/ROCK2 signaling is altered upon TRIM67 ectopic expression, pointing to the underlying mechanism for TRIM67-induced blebbing. Phenotypically, TRIM67 expression resulted in higher cell motility and reduced cell adherence. In orthotopic implantation models of patient-derived oligodendrogliomas, TRIM67 accelerated tumor growth, reduced overall survival, and led to increased vimentin expression at the tumor margin.ConclusionsTaken together, our results demonstrate that upregulated TRIM67 induces blebbing-based rounded cell morphology through Rho GTPase/ROCK-mediated signaling thereby contributing to glioma pathogenesis.
| S-EPMC10237422 | biostudies-literature
Project description:Glial cell-derived brain tumors (gliomas) are devastating diseases without effective curative therapies. Gliomas are classified according to various schemes including the cancer-initiating cell type, World Health Organization tumor grades, and genetic markers such as Isocitrate dehydrogenase (IDH) mutations and chromosomal 1p/19q codeletion status. Genomics, transcriptomics and methylomics approaches are emerging as powerful means to refine classification. However, various aspects of cancer biology are solely reflected on the proteomelevel. Here, we employ mass spectrometry (MS) to characterize the proteomes and phospho-proteomes of IDHmut glioma entities with and without 1p/19q codeletion, IDHwt gliomas and control tissue from a total of 42 patients. Our data-dependent acquisition MS workflow on average quantifies more than 5000 proteins and 3000 phospho-sites per sample of formalin-fixed paraffin-embedded (FFPE) brain sections. The tumor proteomes reflected genetic alterations such as the loss of chromosome 1p/19q proteins, the loss of ATRX in non-codeletion IDHmut glioma, and the frequent loss and amplification of chromosomes 10 and 7, respectively,in IDH-wild type glioma. Nevertheless, 1p/19q codeletion status was not the major determinant of IDHmut glioma proteomes. Instead, the proteome profiles suggest an alternative classification of IDHmut gliomas that correlates with the loss of mitochondrial DNA-encoded proteins, the abundance of respiratory chain proteins, a distinct tumor suppressor and oncoprotein profile, an extracellular matrix signature, and alterations in the phospho-proteome. Moreover, the glioma association of numerous proteins implicated in other cancers by this dataset provides a resource for further mechanistic investigation of glioma genesis and progression.
2022-11-09 | PXD024427 | Pride