Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA137853 | ENA |
REPOSITORIES: ENA
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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
2011-03-14 | E-GEOD-27931 | biostudies-arrayexpress
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.
2011-03-14 | GSE27931 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE11240: An RNAi Screen of Chromatin Proteins Identifies Tip60-p400 as a Regulator of Embryonic Stem Cell Identity, Experiment A GSE11241: An RNAi Screen of Chromatin Proteins Identifies Tip60-p400 as a Regulator of Embryonic Stem Cell Identity, Experiment B Keywords: SuperSeries Refer to individual Series
2008-07-11 | E-GEOD-11243 | biostudies-arrayexpress
Project description:Epigenetic control of neural stem/progenitor cell fate is fundamental to achieve a fully brain architecture. Two intrinsic programs regulate neurogenesis, one by epigenetic-mediated gene transcription and another by cell cycle control. Whether and how these two are coordinated to determine temporally and spatially neural development remains unknown. Here we show that deletion of Trrap (Transcription translation associated protein), an essential cofactor for HAT (histone acetyltransferase), leads to severe brain atrophy due to a combination of cell death and a blockade of neuron production. Specifically, Trrap deletion forces differentiation of apical progenitor (AP) fate into basal progenitors (BP) and neurons thereby limiting the total neurogenic production. Despite TrrapM-bM-^@M-^Ys general role in transcriptional regulation, a genome-wide transcriptome analysis of neuroprogenitors identified the cell cycle regulators that are specifically affected by Trrap deletion. Furthermore, E2F-dependent recruitment of HAT and transcription factors to the promoter of cell cycle regulators is impaired in Trrap-deleted neuroprogenitors. Consistent with these molecular changes, Trrap deletion lengthens particularly G1 and S phases in APs in vivo. Therefore, our study reveals an essential and a distinct function of Trrap-HAT in regulation of cell cycle progression that is required for proper determination of neuroprogenitor fate. Determine gene transcriptions by comparing Trrap-deleted and wild type samples
2014-05-01 | E-GEOD-43650 | biostudies-arrayexpress
Project description:Brain tumor initiating cell response to microglia
| PRJNA226782 | ENA
Project description:Determination of the mechanism by which microglia regulate growth of brain tumor initiating cells (BTICs) and differentiation. Results identify the factors involved in the regulation and provide mechanistic basis. We subjected brain tumor initiating cells to microarray to determine the genes involved in BTICs growth and differentiation when exposed to microglia conditioned medium (MCM) for 6h.
2013-11-06 | GSE52127 | GEO
Project description:Intra-tumor heterogeneity of tumor-initiating cell (TIC) activity drives colorectal cancer (CRC) progression and therapy resistance. Here, we used single-cell mRNA-sequencing (scRNA-seq) of patient-derived CRC models to decipher distinct cell subpopulations based on their transcriptional profiles. Cell type-specific expression modules of stem-like, transit amplifying-like, and differentiated CRC cells resemble differentiation states of normal intestinal epithelial cells. Strikingly, identified subpopulations differ in proliferative activity and metabolic state. In summary, we here show at single-cell resolution that transcriptional heterogeneity identifies functional states during TIC differentiation. Targeting transcriptional states associated to cancer cell differentiation might unravel vulnerabilities in human CRC.
2021-05-07 | PXD018230 | Pride
Project description:Epigenetic control of neural stem/progenitor cell fate is fundamental to achieve a fully brain architecture. Two intrinsic programs regulate neurogenesis, one by epigenetic-mediated gene transcription and another by cell cycle control. Whether and how these two are coordinated to determine temporally and spatially neural development remains unknown. Here we show that deletion of Trrap (Transcription translation associated protein), an essential cofactor for HAT (histone acetyltransferase), leads to severe brain atrophy due to a combination of cell death and a blockade of neuron production. Specifically, Trrap deletion forces differentiation of apical progenitor (AP) fate into basal progenitors (BP) and neurons thereby limiting the total neurogenic production. Despite Trrap’s general role in transcriptional regulation, a genome-wide transcriptome analysis of neuroprogenitors identified the cell cycle regulators that are specifically affected by Trrap deletion. Furthermore, E2F-dependent recruitment of HAT and transcription factors to the promoter of cell cycle regulators is impaired in Trrap-deleted neuroprogenitors. Consistent with these molecular changes, Trrap deletion lengthens particularly G1 and S phases in APs in vivo. Therefore, our study reveals an essential and a distinct function of Trrap-HAT in regulation of cell cycle progression that is required for proper determination of neuroprogenitor fate.
2014-05-01 | GSE43650 | GEO
Project description:Metastatic relapse of breast cancer and other tumor types usually occurs several years after surgical resection of the primary tumor. Early dissemination of tumor cells followed by an extended period of dormancy is thought to explain this prevalent clinical behavior. By using a gain-of-function retroviral cDNA screen in the mouse, we found that Coco, a secreted antagonist of TGF-beta ligands, induces solitary mammary carcinoma cells that have extravasated in the lung stroma to exit from dormancy. Mechanistic studies demonstrate that Coco awakens dormant metastasis-initiating cells by blocking stroma-derived Bone Morphogenetic Proteins. Inhibition of canonical BMP signaling reverses the commitment to differentiation of these cells and enhances their self-renewal and tumor-initiation capacity. Expression of Coco induces a discrete gene expression signature strongly associated with metastatic relapse to the lung but not to the bone or brain in primary patientsâ samples. Accordi ngly, silencing of Coco does not inhibit metastasis to the bone or brain in mouse models. These findings suggest that metastasis-initiating cells require the self-renewal capability typically associated with stem cells in order to exit from dormancy and identify Coco as a master regulator of this process. The Affymetrix HG-U133A and Agilent platforms, which were used to build MSK82 [GSE2603], EMC192 [GSE12276], EMC286 [GSE2034], and NKI295 [van 't Veer et al., 2002; van de Vijver et al.,2002; Fan et al., 2006] datasets, do not contain probes for Coco, preventing a direct analysis of the correlation of the expression of Coco with metastatic relapse. We therefore examined the changes in gene expression caused by silencing of Coco in MDA-MB231 cells in vitro and used the resulting signature as a proxy of Coco expression. Compare the gene expression profile between shscramble with shCoco knockingdown MDA-MB231 cells Coco shRNA #2 corresponds to TRCN0000149666 and Coco shRNA #4 corresponds to TRCN0000148148.
2012-08-16 | E-GEOD-28049 | biostudies-arrayexpress