Engineered Nanointerfaces for Microfluidic Isolation and Molecular Profiling of Tumor-specific Extracellular Vesicles
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE106804 | GEO | 2017/12/01
SECONDARY ACCESSION(S): PRJNA418103
REPOSITORIES: GEO
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Project description:Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor. The brain-infiltrative character of glioblastoma makes complete surgical removal of the tumor impossible and neither radiation nor current chemotherapy provide cure. Recent evidence shows that glioblastoma multiforme consists of heterogeneous cell populations which differ in tumor-forming potential. Enriched tumor-initiating capacity has been linked to poorly differentiated glioblastoma cells sharing features with neural stem cells. Thus, these cells are important targets for new therapeutic strategies. We aim to identify novel targets controlling maintenance and differentiation in glioblastoma-initiating cells through high throughput screening. To this end, we utilized libraries of small chemical compounds and small interference RNAs in combination with automated imaging and data analysis. Patient-derived glioblastoma cells were expanded and characterized using neural stem cell conditions. In culture, the cells showed low differentiation but expression of neural stem cell markers such as Nestin and Sox2. Upon intracranial injection into SCID mice these cells gave rise to tumors displaying the hallmarks of the human disease. Differentiation of glioblastoma-initiating cells (for example elicited through bone morphogenetic protein, BMP) was associated with strong morphological changes. Hence, cellular morphology, as well as markers specific for differentiation or death were used as screen readout. Lentiviral RNA interference-based screening yielded several gene knockdowns leading to ‘forced’ differentiation of glioblastoma-initiating cells. For example, knockdown of TRRAP (transformation/transcription domain associated protein) led to strongly increased differentiation and loss of proliferative and self-renewing capacity in these cells. TRRAP is an adapter protein implicated in oncogenic transformation through c-MYC transcription activation, also participating in chromatin remodeling and DNA repair. Glioblastoma-initiating cells with reduced TRRAP displayed increased apoptosis upon treatment with the genotoxic agent temozolomide. In vivo, Trapp knockdown cells were not able to give rise to glioblastoma upon transplantation into the brain of SCID mice. Together, these findings support a crucial role for TRRAP in maintenance and tumorigenicity of glioblastoma-initiating cells and might offer future therapeutic options. Two treatments compared to control: two different shRNA sequences for TRRAP were compared to a control shRNA sequence in their effects on global transcription in brain tumor initiating cells
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Project description:Glioblastoma multiforme (GBM) is characterized by the close relationship of glioma stem cells (GSC) with aberrant vascularization. It has been established that GSC-derived extracellular vesicles (GSC-EVs) and their cargoes are proangiogenic in vitro. To elucidate gene regulatory mechanisms of neovascularization both in vitro and in vivo, we performed RNA-seq and DNA methylation profiling of the response of human brain endothelial cells to GSC-EVs as well as histoepigenetic analysis of GBM molecular profiles in the TCGA collection. The gene regulatory responses showed a footprint of post-transcriptional gene silencing by EV-derived miRNAs. Remarkably, EVs and normal vascular growth factors stimulated highly distinct gene regulatory responses, both converging on angiogenesis, providing exciting new insight into targetable angiogenic signaling in GBM.
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Project description:Glioblastoma multiforme (GBM) is characterized by the close relationship of glioma stem cells (GSC) with aberrant vascularization. It has been established that GSC-derived extracellular vesicles (GSC-EVs) and their cargoes are proangiogenic in vitro. To elucidate gene regulatory mechanisms of neovascularization both in vitro and in vivo, we performed RNA-seq and DNA methylation profiling of the response of human brain endothelial cells to GSC-EVs as well as histoepigenetic analysis of GBM molecular profiles in the TCGA collection. The gene regulatory responses showed a footprint of post-transcriptional gene silencing by EV-derived miRNAs. Remarkably, EVs and normal vascular growth factors stimulated highly distinct gene regulatory responses, both converging on angiogenesis, providing exciting new insight into targetable angiogenic signaling in GBM.
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Project description:Glioblastoma multiforme (GBM) is characterized by the close relationship of glioma stem cells (GSC) with aberrant vascularization. It has been established that GSC-derived extracellular vesicles (GSC-EVs) and their cargoes are proangiogenic in vitro. To elucidate gene regulatory mechanisms of neovascularization both in vitro and in vivo, we performed RNA-seq and DNA methylation profiling of the response of human brain endothelial cells to GSC-EVs as well as histoepigenetic analysis of GBM molecular profiles in the TCGA collection. The gene regulatory responses showed a footprint of post-transcriptional gene silencing by EV-derived miRNAs. Remarkably, EVs and normal vascular growth factors stimulated highly distinct gene regulatory responses, both converging on angiogenesis, providing exciting new insight into targetable angiogenic signaling in GBM.
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Project description:TCGA Analysis of RNA Expression for Glioblastoma Multiforme Using Affymetrix HT_HG-U133A gabri-00003 Assay Type: Gene Expression Provider: Affymetrix Array Designs: HT_HG-U133A Organism: Homo sapiens (ncbitax) Tissue Sites: Brain Material Types: synthetic_RNA, organism_part, solid_tumor, total_RNA, cell Disease States: GLIOBLASTOMA MULTIFORME, NOT SPECIFIED
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Project description:Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor. The brain-infiltrative character of glioblastoma makes complete surgical removal of the tumor impossible and neither radiation nor current chemotherapy provide cure. Recent evidence shows that glioblastoma multiforme consists of heterogeneous cell populations which differ in tumor-forming potential. Enriched tumor-initiating capacity has been linked to poorly differentiated glioblastoma cells sharing features with neural stem cells. Thus, these cells are important targets for new therapeutic strategies. We aim to identify novel targets controlling maintenance and differentiation in glioblastoma-initiating cells through high throughput screening. To this end, we utilized libraries of small chemical compounds and small interference RNAs in combination with automated imaging and data analysis. Patient-derived glioblastoma cells were expanded and characterized using neural stem cell conditions. In culture, the cells showed low differentiation but expression of neural stem cell markers such as Nestin and Sox2. Upon intracranial injection into SCID mice these cells gave rise to tumors displaying the hallmarks of the human disease. Differentiation of glioblastoma-initiating cells (for example elicited through bone morphogenetic protein, BMP) was associated with strong morphological changes. Hence, cellular morphology, as well as markers specific for differentiation or death were used as screen readout. Lentiviral RNA interference-based screening yielded several gene knockdowns leading to ‘forced’ differentiation of glioblastoma-initiating cells. For example, knockdown of TRRAP (transformation/transcription domain associated protein) led to strongly increased differentiation and loss of proliferative and self-renewing capacity in these cells. TRRAP is an adapter protein implicated in oncogenic transformation through c-MYC transcription activation, also participating in chromatin remodeling and DNA repair. Glioblastoma-initiating cells with reduced TRRAP displayed increased apoptosis upon treatment with the genotoxic agent temozolomide. In vivo, Trapp knockdown cells were not able to give rise to glioblastoma upon transplantation into the brain of SCID mice. Together, these findings support a crucial role for TRRAP in maintenance and tumorigenicity of glioblastoma-initiating cells and might offer future therapeutic options.
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2023-06-01 | E-MTAB-12473 | biostudies-arrayexpress
Project description:glioblastoma multiforme genomic profiling by single nucleotide polymorphism microarray<br><br>Human GBM (glioblastoma multiforme)cell lines (U87, U118, U138, U343, U373, T98G) were maintained in Dulbecco's modified Eagle's medium with 10 % fetal calf serum, 10 U/ml penicillin-G, and 10 mg/ml streptomycin. All cells were incubated at 37 oC in 5% CO2.<br><br>Four primary GBM explants were established from patients with glioblastoma multiforme undergoing surgery as following described: Tumor specimens were immediately transported to the laboratory, finely minced to single cell suspension and cultured in complete medium [Ham's F-12/DME High Glucose medium containing 10% fetal calf serum, 10 U/ml penicillin-G, and 10 mg/ml streptomycin and 2 mM glutamax-1 into 100 cm2 tissue culture plastic dishes the second passage. All cells were incubated at 37 oC in 5% CO2.<br><br>GBM (glioblastoma multiforme) tissue samples were quick frozen. <br><br>Standard proteinase K-phenol-chloroform extraction method was used to extract DNA from GBM samples, cell lines and explants.<br><br>The matched peripheral blood data can be used as normalized data for their matched tumor tissue data. <br><br>The cell lines samples and two explants without normalized data, but they can be normalized by one of the peripheral blood DNA data.
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