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SRP077649
Caenorhabditis elegans
12 Downloadable Samples
Illumina HiSeq 2000
Description
RNA-Seq analysis was performed to assess how a glucose-supplemented diet and/or a hyl-2 mutation altered the transcriptome. Comparison analysis of transcripts associated with anoxia sensitive animals (hyl-2(tm2331) mutation or a glucose diet) revealed 199 common transcripts encoded by genes with known or predicted functions involving innate immunity, cuticle function (collagens) or xenobiotic and endobiotic phase I and II detoxification system. Overall design: mRNA profiles of OP50-fed C. elegans, glucose-fed C. elegans (N2 strain), OP50-fed C. elegans altered in ceramide metabolism (due to a hyl-2(tm2031) mutation), and glucose-fed C. elegans altered in ceramide metabolism were generated by RNA-Seq, in triplicate, using an Illumina HiSeq2000. Transcriptome data were then used for a comprehensive quantitative analysis of differential gene regulation in hyl-2(tm2031) and glucose-fed C. elegans.
Publication Title
Glucose or Altered Ceramide Biosynthesis Mediate Oxygen Deprivation Sensitivity Through Novel Pathways Revealed by Transcriptome Analysis in Caenorhabditis elegans.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 18 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
A chromosomal translocation fusion gene product EWS-WT1 is the defining genetic event in Desmoplastic Small Round Cell Tumor (DSRCT), a rare but aggressive tumor with a high rate of mortality. EWS-WT1 oncogene acts as an aberrant transcription factor that drives tumorigenesis, but the mechanism by which EWS-WT1 causes tumorigenesis is not well understood. To delineate the oncogenic mechanisms, we generated the EWS-WT1 fusion in the mouse using a gene targeting (knock-in) approach, enabling physiologic expression of EWS-WT1 under the native Ews promoter. We derived mouse embryonic fibroblasts (MEFs) and performed genome-wide expression profiling to identify transcripts directly regulated by EWS-WT1. Remarkably, expression of EWS-WT1 led to a dramatic induction of many neuronal genes. Notably, a neural reprogramming factor, ASCL1 (achaete-scute complex-like 1), was highly induced by EWS-WT1 in MEFs and in primary DSRCT. Further analysis demonstrated that EWS-WT1 directly binds to the proximal promoter region of ASCL1 and activates its transcription through multiple WT1-responsive elements. Depletion of EWS-WT1 in a DSRCT cell line resulted in severe reduction in ASCL1 expression and cell viability. Remarkably, when stimulated with neuronal induction media, cells expressing EWS-WT1 expressed neural markers and generated neurite-like projections. These results demonstrate for the first time that EWS-WT1 activates neural gene expression and is capable of directing partial neuronal differentiation, likely via ASCL1. These findings suggest that stimulating DSRCT tumor cells with biological or chemical agents that promote neural differentiation might be a useful approach to develop novel therapeutics against this incurable disease.
Publication Title
EWS-WT1 oncoprotein activates neuronal reprogramming factor ASCL1 and promotes neural differentiation.
Sample Metadata Fields
Specimen part, Time
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Identify Wnt3A responsive signature in lung adenocarcinoma cells
Publication Title
WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The overall goal and objective is to study the degree to which PAX3-FKHR accounts for differences between ARMS and ERMS by expressing a construct (termed P3FK/ER) consisting of PAX3-FKHR joined to the estrogen receptor ligand binding domain in an ERMS cell culture system.
Publication Title
Identification of PAX3-FKHR-regulated genes differentially expressed between alveolar and embryonal rhabdomyosarcoma: focus on MYCN as a biologically relevant target.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Ewing sarcoma family tumors (ESFTs) are aggressive tumors of putative stem cell origin for which prognostic biomarkers and novel treatments are needed. We have previously shown that the polycomb gene BMI-1 functions as an oncogene in ESFT. In several human cancers, high expression of BMI-1 is associated with poor outcome. For the current study, we evaluated the significance of variable BMI-1 expression levels in a large cohort of primary ESFT. Immunohistochemical staining of 130 tumors revealed that BMI-1 is over-expressed by the vast majority of ESFT. However, in 20% of cases, BMI-1 levels are low to undetectable. Significantly, although clinical presentation and outcome were found to be similar between BMI-1-high and BMI-1-low tumors, gene expression profiling studies showed marked differences in their respective gene expression profiles. Gene specific enrichment analysis identified that several cancer-associated canonical biologic pathways, including IGF1, mTOR and WNT, are significantly down-regulated in BMI-1-low compared to BMI-1-high tumors. Consistent with these in vivo data, in vitro studies of IGF1-R inhibition showed that the growth inhibitory effects of IGF1-R blockade are diminished in BMI-1-low ESFT cells. ESFT that do not over-express BMI-1 represent a novel subclass with a distinct molecular profile and altered activation of cancer-associated pathways.
Publication Title
Ewing tumors that do not overexpress BMI-1 are a distinct molecular subclass with variant biology: a report from the Children's Oncology Group.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
We have discovered frequent genetic inactivation of the STAG2 gene in diverse human cancers including glioblastoma, Ewing's sarcoma, and melanoma. STAG2 encodes a subunit of the sister chromatid cohesion complex called the "cohesin complex" that is responsible for the cohesion of sister chromatids following DNA replication and is cleaved at the metaphase to anaphase transition to enable chromosome segregation into daughter cells. Interestingly, the cohesin complex has also been implicated as a regulator of chromatin architecture and transcription. To determine the functional significance of STAG2 inactivation in cancer pathogenesis, we used somatic cell gene targeting to correct the endogenous mutations of STAG2 in two aneuploid human glioblastoma cell lines, H4 and 42MGBA. Similarly, somatic cell gene targeting was also used to introduce a nonsense mutation into codon 6 of the endogenous wild-type allele of STAG2 in HCT116 cells, a near-diploid human colorectal cancer cell line with stable karyotype. Expression profiling of these three paired sets of STAG2-proficient and deficient cells demonstrated that STAG2 does not play a global role in transcriptional regulation nor does it recurrently modulate the expression of specific tumor-promoting or suppressing genes.
Publication Title
Mutational inactivation of STAG2 causes aneuploidy in human cancer.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Constitutive activation of EGFR- and NF-kB-dependent pathways is a hallmark of cancer, yet signaling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as a BCL-3- and p65-dependent gene in transformed keratinocytes. KIAA1199 expression is enhanced upon human papillomavirus (HPV) infection and is aberrantly expressed in clinical cases of cervical (pre)neoplastic lesions. Mechanistically, KIAA1199 binds Plexin A2 and protects from Semaphorin 3A-mediated cell death by promoting EGFR stability and signaling. Moreover, KIAA1199 is an EGFR-binding protein and KIAA1199 deficiency impairs EGF-dependent Src, MEK1 and ERK1/2 phosphorylations. Therefore, EGFR stability and signaling to downstream kinases requires KIAA1199. As such, KIAA1199 promotes EGF-mediated epithelial-mesenchymal transition (EMT). Taken together, our data define KIAA1199 as an oncogenic protein induced by HPV infection and constitutive NF-kB activity that transmits pro-survival and invasive signals through EGFR signaling.
Publication Title
NF-κB-induced KIAA1199 promotes survival through EGFR signalling.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 53 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 10 Downloadable Samples
- Illumina HiSeq 2000
Description
Gene fusions arising from chromosomal translocations are key oncogenic drivers in soft tissue sarcomas but little is known about how they exert their oncogenic effects. Our study explores the molecular mechanisms by which the SS18-SSX fusion oncoprotein subverts epigenetic mechanisms of gene regulation to drive synovial sarcoma. Using functional genomics, we identify KDM2B – a histone demethylase and core component of a non-canonical Polycomb Repressive Complex 1 (PRC1.1) – as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands genome-wide. Via KDM2B, SS18-SSX binds and aberrantly activates expression of a series of developmentally regulated transcription factors that would otherwise be targets of polycomb-mediated repression, which is restored upon KDM2B depletion leading to irreversible mesenchymal differentiation. Thus, SS18-SSX de-regulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression. Overall design: RNA-Seq of human synovial sarcoma cells (HS-SY-II) in control cells (Ren.173) and upon knockdown of SS18-SSX1 (SS18.273 and SSX.1274) or of KDM2B (KDM2B. 4395 and KDM2B.4835) in duplicates.
Publication Title
The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma.
Sample Metadata Fields
Subject
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
The highly aggressive muscle cancer alveolar rhabdomyosarcoma (ARMS) is one of the most common soft tissue sarcoma of childhood, yet the outcome for unresectable and metastatic disease is dismal and unchanged for nearly 3 decades. To better understand the pathogenesis of this disease and to facilitate novel preclinical approaches, we previously developed a conditional mouse model of ARMS by faithfully recapitulating the genetic mutations observed in the human disease, i.e. activation of Pax3:Fkhr fusion gene with either p53 or Cdkn2a inactivation. In this report we show that this model recapitulates the immunohistochemical profile and the rapid progression of the human disease. We demonstrate that Pax3:Fkhr expression increases during late preneoplasia, but that tumor cells undergoing metastasis are under apparent selection for Pax3:Fkhr expression. At a whole genome level, a cross-species gene set enrichment analysis and metagene projection study showed that our mouse model is most similar to human ARMS when compared to other pediatric cancers. We have defined an expression profile conserved between mouse and human ARMS as well as a Pax3:Fkhr signature, including the target gene, SKP2. We further identified 7 druggable kinases over-expressed across species. The data affirms the accuracy of this genetically engineered mouse model.
Publication Title
Credentialing a preclinical mouse model of alveolar rhabdomyosarcoma.
Sample Metadata Fields
Disease, Disease stage
View Samples