Genomic landscape of Chordoid Glioma
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ABSTRACT:
PROVIDER: EGAS00001002433 | EGA |
REPOSITORIES: EGA
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Project description:Genomic Landscape of Chordoid Glioma
| EGAD00010001571 | EGA
Project description:A highly penetrant heterozygous mutation in PRKCA was found recently in chordoid glioma. To establish whether this mutant of PKCapha was a driver of tumour formation or maintenance in vivo, knock-in mice were generated. The constitutive, heterozygous expression of the Prkca D463H mutant in mice provoked the development of bilateral hindlimb chondrosarcomas and early neonatal mortality. The lack of activity of the D463H mutant was not the trigger of the phenotype as heterozygous knock-in of the related inactivating mutation D463N produced offspring indistinguishable from parental strains. Moreover, this surprising distinction between D463H and D463N mutations did not reflect a selective lack of dominance for the D463N mutation over the wild type (WT) allele since homozygous expression of this mutation was phenotypically WT. In cell culture, the D463H mutant expression, localisation and downregulation behaviours closely mimicked that of the WT, with the D463N mutant displaying some subtle differences. Biochemically, both the D463H and D463N mutants were shown to be inactive, although based on thermal shift assays the D463N mutant had reduced ATP affinity compared to WT or D463H proteins. Using induced transcriptional changes as a functional readout, altered mRNA expression indicates that the D463H acts as a dominant gain-of-function PKC mutant, despite a complete lack of intrinsic kinase activity; transcriptional changes induced by the D463N mutant were distinct from both the WT and D463H mutant. These findings suggest a model in which there is a non-catalytic effector function of PKCalpha which it is presumed operates through protein-protein interactions, as evidenced here by TurboID proximity labelling. The penetrant selection of the specific inactivating D463H mutation in chordoid glioma and the distinction with the D463N mutation indicates that this is conformationally sensitive. The properties characterised suggest this is driven by ATP binding and by inference, in this tissue context, the catalytic activity of this kinase acts as an autoregulatory negative feedback control.
2024-06-12 | GSE269531 | GEO
Project description:The penetrant chordoid glioma PRKCA mutation is an oncogenic gain-of-function kinase inactivation eliciting early onset chondrosarcoma in mice
| PRJNA1122210 | ENA
Project description:Natural non-coding antisense transcripts (ncNATs) are long non-coding RNAs (lncRNA) transcribed from the opposite strand of a separate protein coding or non-coding gene and can affect the overlapped gene expression through epigenetic, transcriptional, post-transcriptional and/or translational modulations. ncNATs can influence cancerous cell proliferation, migration and therapeutic resistance. Recently, growing numbers of ncNATs were shown to be dysregulated in cancerous cells, however, actual impact of ncNATs on cancer progression remains largely unknown. We performed RNA-seq on post-surgical tumor samples from 26 glioma patients, and normal brain tissue.
2023-02-24 | GSE219250 | GEO
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.
2015-04-07 | E-GEOD-61080 | biostudies-arrayexpress
Project description:Our preliminary data demonstrate that malignant gliomas in both human GBM and mouse models display regular anatomical structures, ‘oncostreams’; we interpret these as a manifestation of GBM self-organization. Oncostreams’ presence correlates with tumor malignancy and parenchymal invasion. Molecular signaling pathways that regulate oncostreams’ organization and function, however, remain unknown. We will test the hypothesis that oncostreams’ present in mouse intracranial glioma model have a characteristic transcriptome that differs from surrounding tumor, and to identify critical genes that regulate oncostreams function.
2021-11-18 | GSE188970 | GEO
Project description:A comprehensive study is conducted to inspect the role and function of methyl-CpG-binding domain protein 3 (MBD3) in human malignant glioma, as well as to test its potential as a novel prognostic biomarker. Using whole-genome microarray for transcriptome, the MBD3-mediated epigenetic regulation in glioma was profiled.
2016-11-08 | GSE79876 | GEO
Project description:Chordoid glioma is a rare brain tumor thought to arise from specialized ependymal cells of the lamina terminalis along the anterior wall of the third ventricle. We performed targeted next-generation sequencing of approximately 500 cancer-associated genes on a cohort of 13 chordoid gliomas and identified a recurrent D463H missense mutation in the PRKCA gene in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCa).
| EGAS00001002733 | EGA
Project description:Gliomas are the most devastating of primary adult malignant brain tumors. These tumors are highly infiltrative and can arise from cells with extensive self-renewal capability and chemoresistance, frequently termed glioma-propagating cells (GPCs). GPCs are thus the plausible culprits of tumor recurrence. Treatment strategies that eradicate GPCs will greatly improve disease outcome. Such findings support the use of GPCs as in vitro cellular systems for small molecule screening. However, the nuances in utilizing GPCs as a cellular screening platform are not trivial. These slow-growing cells are typically cultured as suspension, spheroid structures in serum-free condition supplemented with growth factors. Consequently, replenishment of growth factors throughout the screening period must occur to maintain cells in their undifferentiated state, as the more lineage-committed, differentiated cells are less tumorigenic. We will present a case study of a small molecule screen conducted with GPCs and explain how unique sphere activity assays were implemented to distinguish drug efficacies against the long-term, self-renewing fraction, as opposed to transient-amplifying progenitors, latter of which are detected in conventional viability assays. We identified Pololike kinase 1 as a regulator of GPC survival. Finally, we leveraged on public glioma databases to illustrate GPC contribution to disease progression and patient survival outcome. Total RNA from primary neurosphere culture of brain tumor specimens were hybridized in baseline condition. Specimens were obtained from 11 patients and replicate arrays were performed for all 11 neurosphere cultures.
2012-08-01 | E-GEOD-36782 | biostudies-arrayexpress
Project description:This work lays the foundation for the intratumoral immune infiltrates of glioma patients analyzed at a single cell level with the dual purpose of establishing the relevance of a new mouse model of GBM with regard to the patient disease. The aim of this study was to determine the level of concordance between the spontaneous and implanted Qk/trp53/Pten (QPP) triple-knockout mouse GBM model and human glioma samples in regard to their immune infiltrates.We analyzed a cohort of fifteen spontaneous QPP mice, nine implanted QPP mice and 10 glioma patients histopathologically. Furthermore, we analyzed three spontaneous QPP mice, thee implanted QPP mice, and 10 glioma patients by single cell RNA sequencing. We found that the QPP model recapitulates human GBM regarding the major immune components including a predominantly myeloid cell population of monocytes, macrophages, and resting dendritic cells, with minor populations of T, B, and NK cells. In addition, the complexity of the myeloid cell populations is preserved between the QPP model and the human disease.
2021-07-21 | GSE147275 | GEO