Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Comparison of EGF and PDGF driven glioblastomas.

ABSTRACT: Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor. Epidermal growth-factor (EGF) and platelet-derived growth-factor (PDGF) receptors are frequently amplified and/or possess gain-of-function mutations in these tumors. Despite years of research into tyrosine-kinase inhibitors, clinical trials have shown disappointing efficacy. One of the underlying reasons is intra-tumor heterogeneity. To assess the effect of intra-tumor heterogeneity on gene expression, we derived a general approach to map single-cell expression profiles to sequentially-acquired mutations identified from exome sequencing. Using 288 single cells, we constructed high-resolution phylogenies of EGF-driven and PDGF-driven GBMs, modeling transcriptional kinetics during tumor evolution. A deletion in a PDGF-receptor domain involved in dimerization correlated to an up-regulation of the PI3K/AKT pathway in a proneural GBM, and ectopic expression of this mutant PDGFRA in vitro enhanced proliferation and invasiveness. Descending the phylogenetic tree of the PDGFR-driven tumor corresponded to a progressive induction of an oligodendrocyte progenitor-like cell type that expresses growth and angiogenic factors. In contrast, phylogenetic analysis of an EGFR-amplified tumor showed a gradual up-regulation of pro-invasive genes.

PROVIDER: EGAS00001001900 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Json Xml

Similar Datasets

Glioblastoma Genetic Drivers Dictate the Function of Tumor-Associated Macrophages/Microglia and Responses to CSF1R Inhibition

Project description:Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting.We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment cellular compositions and functions in PDGFB- and RAS-driven gliomas. We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas.Our work identify functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.

2021-10-08 | GSE185420 | GEO

Transcription profiling of human glioma cell lines reveals CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and expression profiles

Project description:We cultured tumor cells from 22 GBM under medium conditions favoring the growth of neural stem cells. 11 out of 15 primary GBM contained a significant CD133+ subpopulation that comprised cells showing all hallmarks of neural stem cells. Cell lines derived from these CD133+ GBM showed a neurosphere-like, non-adherent growth pattern. In contrast, 4 out of 15 cell lines derived from primary GBM grew adherent in vitro and were driven by CD133- tumor cells that fulfilled stem cell criteria. In vivo, these GBM were characterized by a significantly lower proliferation index but similar GFAP staining as compared to CD133+ GBM. Gene arrays from 2x3 representative cells lines are given. Experiment Overall Design: Human glioblastoma cells cultured in DMEM supplemented with EGF, FGF, LIF, B27.

2007-11-01 | E-GEOD-7181 | biostudies-arrayexpress

Transcription profiling by array of human Glioblastoma multiforme (GBM) tumor samples to asses the intra-tumoral heterogeneity at the gene expression level

Project description:Glioblastoma multiforme (GBM) is a highly heterogeneous disease that shows an enourmous range of genetic abnormalities in comparison to other astrocytic tumors. Intra-patient heterogeneity in GBM has been poorly characterized both at phenotypic and genomic level. During surgical GBM resections, we have extracted between 4 and 8 tumor subsamples from different areas of the malignant tissue that were at least 1cm apart. Our aim to asses the intra-tumoral heterogeneity at the gene expression level to uncover important dynamics underlying GBM progression that may have relevant implication for treatment.

2013-02-16 | E-MTAB-1129 | biostudies-arrayexpress

Intra-Tumor DNA Methylation Heterogeneity in Glioblastoma; Implications for DNA Methylation-based Classification

Project description:Background: A feature of glioblastoma (GBM) is the cellular and molecular heterogeneity, both within and between tumors. This variability results in a risk for sampling bias and potential tumor escape from future targeted therapy. Heterogeneous gene expression within GBM is well documented, but little is known regarding the epigenetic heterogeneity. We therefore aimed to profile the intra-tumor DNA methylation heterogeneity in GBM. Methods: 3-4 biopsies per tumor from spatially separated regions were collected from 12 GBM patients. We performed genome-wide DNA methylation analysis (~850,000 CpG sites) and compared inter- and intra-tumor variation. Results: All samples were classified as GBM IDH wt or IDH mutated by DNA methylation profiling, but the GBM subtype differed within five tumors. Some GBM samples exhibited higher DNA methylation differences within tumors than between, and many CpG sites (mean: 17,000) had different methylation levels within the tumors. Conclusions: We demonstrated that intra-tumor DNA methylation heterogeneity is a feature of GBM. Although all biopsies were classified as GBM IDH wt/mutated by DNA methylation analysis, the assigned subtype differed in samples from the same patient. The observed DNA methylation heterogeneity within tumors is important to consider for methylation-based biomarkers and future improvements in stratification of GBM patients.

2019-02-27 | GSE116298 | GEO

Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2 (MDH2)

Project description:Glioblastoma (GBM) ranks among the most lethal of human cancers with current therapies offering only palliation. GBM displays striking intratumoral heterogeneity with diversity of cell state, metabolism, and molecular regulation. Here, we demonstrate that stem-like tumor cells, designated GBM stem cells (GSCs), display higher activity of the malate aspartate shuttle (MAS) through increased expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 reduced GSC proliferation, self-renewal, and in vivo tumor growth. MDH2 targeting induced accumulation of alpha-ketoglutarate (αKG), a critical enzymatic co-factor. Mechanistically, MDH2 regulated post-transcriptional regulation of mRNA, specifically N6-Methyladenosine (m6A) with platelet-derived growth factor receptor- (PDGFR) as a regulated transcript. Leveraging these observations, targeting MDH2 and PDGFR displayed combinatorial efficacy against GSCs. Collectively, these results suggest that stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes that reveal possible therapeutic paradigms.

2024-10-15 | GSE255535 | GEO

CD133+ and CD133- CSC lines in primary human GBM

2007-03-06 | GSE7181 | GEO

DOCK8 is a Novel Regulator of Lysosome Mediated Pancreatic Cancer Invasion

Project description:Amplified lysosome activity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) orchestrated by oncogenic KRAS that mediates tumor progression and metastasis, though the mechanisms underlying this phenomenon remain unclear. Using comparative proteomics, we found that oncogenic KRAS significantly enriches levels of the guanine nucleotide exchange factor (GEF) DOCK8 on lysosomes. Surprisingly, we found that DOCK8 is aberrantly expressed in a subset of PDAC where it promotes cell invasion and proliferation. Further, DOCK8 associates with lysosomes and regulates lysosomal morphology and motility. DOCK8 promotes actin polymerization at the surface of lysosomes, while increasing the levels and proteolytic activity of the lysosomal protease cathepsin B. Depletion of DOCK8 significantly reduces extracellular matrix degradation and impairs the invasive capacity of PDAC cells. Further, CRISPR-based knockout of DOCK8 dramatically reduces tumor size and metastasis in vivo. Together, these findings implicate ectopic expression of DOCK8 as a key driver of KRAS-driven lysosomal regulation, tumor progression, and metastasis.

2023-01-10 | MSV000091036 | MassIVE

Profiling by array of human Glioblastoma multiforme (GBM) tumor samples to asses the intra-tumoral heterogeneity in genomic copy number aberrations

Project description:Glioblastoma multiforme (GBM) is a highly heterogeneous disease that shows an wide range of genetic abnormalities in comparison to other astrocytic tumors. We have extracted between 4 and 8 tumor subsamples from different areas of the malignant tissue that were at least 1cm apart. Our aim to asses the intra-tumoral heterogeneity by comparing copy number aberrations in different tumor areas to uncover important dynamics underlying GBM progression.

2013-02-15 | E-MTAB-1215 | biostudies-arrayexpress

hSETD1A cooperates with beta-catenin to regulate Wnt target genes and control colorectal tumor growth

Project description:Glioblastoma multiforme (GBM) is the most prevalent type of adult brain tumor, and one of the deadliest tumors known to mankind. The genetic understanding of GBM is, however, limited, and the molecular mechanisms which facilitate GBM cell survival and growth within the tumor microenvironment are largely unknown. We applied digital karyotyping and single nucleotide polymorphism (SNP) arrays to screen for copy number changes in GBM samples and found that the most frequently amplified region is at chromosome 7p11.2. The high resolution of digital karyotyping and SNP arrays permits the precise delineation of amplicon boundaries and has enabled identification of the minimal region of amplification at 7p11.2, which contains two genes, EGFR and SEC61γ. SEC61γ encodes a subunit of a heterotrimeric protein channel located in the endoplasmic reticulum (ER). In addition to its high frequency of gene amplification in GBMs, SEC61γ is also remarkably overexpressed in 77% of GBMs, but not in lower-grade gliomas. The siRNA-mediated knockdown of SEC61γ expression in tumor cells led to growth suppression and apoptosis. Furthermore, we showed that pharmacological ER stress agents induce SEC61γ expression in GBM cells. Together, these results indicate that aberrant expression of SEC61γ serves significant roles in GBM cell survival, likely via a mechanism that is involved in the cytoprotective ER stress-adaptive response to the tumor microenvironment.

2013-12-15 | GSE52230 | GEO

Expression changes following siRNA knockdown of ADRM1 in ovarian cell line OAW42

Project description:Knock-down of ovarian cancer amplification target ADRM1 leads to down regulation of GIPC1 and up-regulation of RECK. Among 20q13-amplified genes in ovarian cancer, ADRM1 overexpression was the most highly correlated with amplification, and was significantly upregulated with respect to stage, recurrence and metastasis. In addition, overexpression of ADRM1 correlated significantly with shorter time to recurrence and overall survival. Herein, array-CGH and microarray expression of ovarian cancer cell lines, provides evidence consistent with the primary tumor data that ADRM1 is a 20q13 amplification target. Knock-down of ADRM1 in amplified ovarian cell line OAW42 results in down-regulation of growth factor GIPC1 and up-regulation of tumor-suppressor RECK RNA and protein. In our dataset of 141 ovarian primary tumors, ADRM1 overexpression significantly correlates with GIPC1 overexpression. In addition, there is a significant anticorrelation between ADRM1 overexpression and RECK expression. Further research is necessary to determine whether targeting knock-down of ADRM1 in 20q13-amplified ovarian cancers results in growth inhibition and tumor suppression via downstream targets GIPC1 and RECK.

2011-01-14 | GSE26634 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data