Single cell RNA-seq of brain glioblastoma samples
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE162631 | GEO | 2021/07/08
REPOSITORIES: GEO
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Project description:Medulloblastomas (MBs) and Glioblastomas (GBMs) are high-incidence central nervous system tumors. Different origin sites and changes in the tissue microenvironment have been associated with onset and progression. Here, we describe differences between the ECM signature of these tumors. We compared the proteomic profiles of MB and GBM decellularized tumor samples among each other and their normal decellularized brain site counterparts. Our analysis reveals that 19 proteins were differentially expressed in MBs, 28 proteins in GBMs, and 11 proteins in both MBs and GBMs. Next, we validated key findings by protein tissue array with 53 MB and 55 GBM cases and evaluated the clinical relevance of the identified differentially expressed proteins through their analysis on publicly available datasets, 763 MB samples from microarray-GSE50161, and 115 GBM samples from RNAseq-TCGA. We report a shift towards a denser fibrillary ECM as well as a clear alteration in the glycoprotein signature, which influences the tumor pathophysiology.
2021-12-30 | PXD023350 | Pride
Project description:Glioblastoma (GBM) is an incurable brain tumor carrying a dismal prognosis, which displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical positions of histone H3.3 (K27, G34) in one-third of pediatric GBM. Here we show that each of these H3F3A mutations defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and are mutually exclusive with IDH1 mutations (characterizing a CpG-Island Methylator Phenotype (CIMP) subgroup). Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM (EGFR amplification, CDKN2A/B deletion) and/or known transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of OLIG1/2 and FOXG1, possibly reflecting different cellular origins. We identified six epigenetic and biological GBM subgroups displaying distinct global DNA methylation patterns, which harbor unique hotspot mutations, DNA copy-number alterations, and transcriptomic patterns. We investigated a subset of childhood (n=59) and adult GBMs (n=77) using the Illumina 450k methylation array. Six non-neoplastic brain tissue samples are included as controls.
2012-10-16 | E-GEOD-36278 | biostudies-arrayexpress
Project description:Glioblastomas (GBMs), which are the most deadly malignant brain tumors of children and adults, infiltrate the brain and grow rapidly, and are resistant to current therapies. Glioblastomas (GBMs) frequently display mutations that activate receptor tyrosine kinases (RTKs), such as EGFR, which are thought to cooperate with additional factors to drive tumorigenesis. To identify and characterize genetic pathways that cooperate with RTKs to drive GBM progression, we performed RNA sequencing on several cell cultures created from surgical specimens from tumors with alterations in RTKs, and these cultures were grown as neurospheres in serum-free media used for normal neural stem/progenitor cell cultures. Under these conditions, GBM cells retain many defining features and mutations found in primary tumors. For comparison, we profiled commercially available human normal neural stem cells (HNPCs), which were grown under the same conditions. Data from these cell cultures was analyzed for transcripts differentially expressed between GBM cells and HNPCs, which showed that GBM cells that show RTK alterations strongly overexpressed the PDGFA and IGF2 secreted factors, which likely cooperate with EGFR to drive tumor progression.
2018-11-20 | GSE122679 | GEO
Project description:Background: Glioblastomas are the most common primary brain tumour in adults. While the prognosis for patients is poor, gene expression profiling has detected signatures that can sub-classify GBMs relative to histopathology and clinical variables. One category of GBM defined by a gene expression signature is termed ProNeural (PN), and has substantially longer patient survival relative to other gene expression-based subtypes of GBMs. Age of onset is a major predictor of the length of patient survival where younger patients survive longer than older patients. The reason for this survival advantage has not been clear. We collected 267 GBM CEL files and normalized them relative to other microarrays of the same Affymetrix platform. 377 probesets on U133A and U133 Plus 2.0 arrays were used in a gene voting strategy with 177 probesets of matching genes on older U95Av2 arrays. Kaplan-Meier curves and Cox proportional hazard analyses were applied in distinguishing survival differences between expression subtypes and age. Results: Here we collected 267 glioblastomas and explore the relationship between gene expression subtype, age at diagnosis, and survival. This meta-analysis of published data in addition to new data confirms the existence of four distinct GBM expression-signatures. Further, patients with PN subtype GBMs had longer survival, as expected. However, the age of the patient at diagnosis is not predictive of survival time when controlled for the PN subtype. Conclusions: The survival benefit of younger age is nullified when patients are stratified by gene expression group. Thus, the main cause of the age effect in GBMs is the more frequent occurrence of PN GBMs in younger patients relative to older patients. Experiment Overall Design: Clinical data including histopathology, age, sex, and survival time from diagnosis were retrieved from 181 glioblastomas which have been reported within previous studies between 2003 and 2006 and for which CEL files (Affymetrix, Santa Clara, CA) were available from the authors. In addition, we collected 86 new patient-unique tumour biopsies from the UCLA Neuro-oncology Program (n = 55) and the Barrow Neurological Institute (n = 31) for a grand total of 267 glioblastomas. Newly acquired tumours were collected through institutional review board approved protocols and assigned WHO grades at UCLA Neuropathology or Barrow Neuropathology by PSM. Time of survival (days), sex, and, age were collected where available. Patient age at the time of diagnosis was available for 239 patients and ranged from 18 to 86 years. Sex of the individual was available for those 239 patients (151 males and 88 females). There were no technical replicates. There were no control or reference samples. No dye swap due to single channel array platforms.
2008-10-26 | E-GEOD-13041 | biostudies-arrayexpress
Project description:Background: Glioblastomas are the most common primary brain tumour in adults. While the prognosis for patients is poor, gene expression profiling has detected signatures that can sub-classify GBMs relative to histopathology and clinical variables. One category of GBM defined by a gene expression signature is termed ProNeural (PN), and has substantially longer patient survival relative to other gene expression-based subtypes of GBMs. Age of onset is a major predictor of the length of patient survival where younger patients survive longer than older patients. The reason for this survival advantage has not been clear. We collected 267 GBM CEL files and normalized them relative to other microarrays of the same Affymetrix platform. 377 probesets on U133A and U133 Plus 2.0 arrays were used in a gene voting strategy with 177 probesets of matching genes on older U95Av2 arrays. Kaplan-Meier curves and Cox proportional hazard analyses were applied in distinguishing survival differences between expression subtypes and age. Results: Here we collected 267 glioblastomas and explore the relationship between gene expression subtype, age at diagnosis, and survival. This meta-analysis of published data in addition to new data confirms the existence of four distinct GBM expression-signatures. Further, patients with PN subtype GBMs had longer survival, as expected. However, the age of the patient at diagnosis is not predictive of survival time when controlled for the PN subtype. Conclusions: The survival benefit of younger age is nullified when patients are stratified by gene expression group. Thus, the main cause of the age effect in GBMs is the more frequent occurrence of PN GBMs in younger patients relative to older patients. Keywords: Gene expression profiling, GBM, glioblastoma, survival, MGMT, VEGFA, EGFR, Temozolomide, Affymetrix
2008-10-10 | GSE13041 | GEO
Project description:Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The basic-helix-loop-helix (bHLH) transcription factors ASCL1 and OLIG2 are dynamically co-expressed in GBMs; however, their combinatorial roles in regulating the plasticity and heterogeneity of GBM cells are unclear. Here, we show that induction of somatic mutations in subventricular zone (SVZ) progenitor cells leads to the dysregulation of ASCL1 and OLIG2, which then function redundantly and are required for brain tumor formation in a mouse model of GBM. Subsequently, the binding of ASCL1 and OLIG2 to each other’s loci and to downstream target genes then determines the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in specifying highly migratory neural stem cell (NSC)/astrocyte-like tumor cell types, which are marked by upregulation of ribosomal protein, oxidative phosphorylation, cancer metastasis, and therapeutic resistance genes.
2024-06-30 | GSE247977 | GEO
Project description:Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The basic-helix-loop-helix (bHLH) transcription factors ASCL1 and OLIG2 are dynamically co-expressed in GBMs; however, their combinatorial roles in regulating the plasticity and heterogeneity of GBM cells are unclear. Here, we show that induction of somatic mutations in subventricular zone (SVZ) progenitor cells leads to the dysregulation of ASCL1 and OLIG2, which then function redundantly and are required for brain tumor formation in a mouse model of GBM. Subsequently, the binding of ASCL1 and OLIG2 to each other’s loci and to downstream target genes then determines the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in specifying highly migratory neural stem cell (NSC)/astrocyte-like tumor cell types, which are marked by upregulation of ribosomal protein, oxidative phosphorylation, cancer metastasis, and therapeutic resistance genes.
2024-06-30 | GSE247650 | GEO
Project description:Frequent discrepancies between preclinical and clinical results of anti-cancer agents demand a reliable translational platform that can precisely recapitulate the biology of human cancers. Another critical unmet need is the ability to predict therapeutic responses for individual patients. Toward this goal, we have established a library of orthotopic glioblastoma (GBM) xenograft models using surgical samples of GBM patients. These patient-specific GBM xenograft tumors recapitulate histopathological properties and maintain genomic characteristics of parental GBMs in situ. Furthermore, in vivo irradiation, chemotherapy, and targeted therapy of these xenograft tumors mimic the treatment response of parental GBMs. We also found that establishment of orthotopic xenograft models portends poor prognosis of GBM patients and identified the gene signatures and pathways signatures associated with the clinical aggressiveness of GBMs. Together, the patient-specific orthotopic GBM xenograft library represent the preclinically and clinically valuable “patient tumor’s phenocopy” that represents molecular and functional heterogeneity of GBMs. aCGH experiments were performed for a human glioblastoma tissue (sample ID: PC-NS08-559) and the matching xenograft tumor tissue using the Agilent Human Whole Genome CGH 244K microarray according to manufacturer's protocol (2-color).
2013-01-18 | E-GEOD-42577 | biostudies-arrayexpress
Project description:Glioblastomas (GBMs) are highly invasive brain tumors replete with brain- and blood-derived macrophages, collectively known as tumor-associated macrophages (TAMs). Targeting TAMs has been proposed as a therapeutic strategy but has thus far yielded limited clinical success in slowing GBM progression, due in part to an incomplete understanding of TAM function in GBM. Here, by using an engineered hyaluronic acid-based 3D invasion platform, patient-derived GBM cells, and multi-omics analysis of GBM tumor microenvironments, we show that M2-polarized macrophages stimulate GBM stem cell (GSC) mesenchymal transition and invasion. We identify TAM-derived transforming growth factor beta induced (TGFβI/BIGH3) as a pro-tumorigenic factor in the GBM microenvironment. In GBM patients, BIGH3 mRNA expression correlates with poor patient prognosis and is highest in the most aggressive GBM molecular subtype. Inhibiting TAM-derived BIGH3 signaling with a blocking antibody or small molecule inhibitor suppresses GSC invasion. Our work highlights the utility of 3D in vitro tumor microenvironment platforms to investigate TAM-cancer cell crosstalk and offers new insights into TAM function to guide novel TAM-targeting therapies.
2023-12-21 | GSE251777 | GEO
Project description:Glioblastoma (GBM) remains a challenging malignancy with dismal prognoses despite aggressive treatment regimens. Intratumoral heterogeneity contributes to therapeutic resistance, with roles for stem cell-like brain tumor initiating cells (GBMs), glioma associated macrophages (GAMs), and communication between them. GAMs are derived from infiltrating lymphocytes, and monocyte migration is increased by GBM cell release of extracellular vesicles, including exosomes. GBM survival is promoted by the glucose transporter GLUT3, which was recently shown to alter macrophage activation states. We found that GBM-derived exosomes contain GLUT3 and that exosomes from GLUT3 expressing GBMs significantly increased monocyte migration in comparison to controls. Monocytes transfected with GLUT3 (but not GLUT1) also had significantly increased migration, demonstrating a direct role for GLUT3 in monocytes migration. Analysis of the transcriptome of exosome treated monocytes demonstrated that exosomes derived from GLUT3 expressing GBMs increasedGDF-15in monocytes. GDF-15 is a known regulator of monocyte migration, and we determined that knockdown of GDF-15 blocked the migration induced by GBM-derived exosomes. As GDF-15 induced monocyte migration is thought to involve MMP12, we next evaluated MMP12 as a potential mediator of the pro-migratory phenotype.MMP12was significantly increased in monocytes upon treatment with exosomes derived from GLUT3 expressing GBMs as was MMP12 activity. Together, our findings suggest a novel mechanism by which GBMs facilitate immune evasion and tumor progression: GBM-derived exosomes transfer GLUT3 to monocytes to increase a GDF-15/MMP12 pathway that promotes monocyte migration. The data also highlight the importance of understanding and targeting cell-cell interactions to improve glioblastoma treatment.
2024-12-01 | GSE274966 | GEO