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GSE69780
Homo sapiens
6 Downloadable Samples
Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Translation initiation factor eIF4E is overexpressed early in breast cancers in association with disease progression and reduced survival. Much remains to be understood regarding the role of eIF4E in human cancer. Using immortalized human breast epithelial cells, we report that elevated expression of elF4E translationally activates the TGF pathway, promoting cell invasion, loss of cell polarity, increased cell survival and other hallmarks of early neoplasia. Overexpression of eIF4E is shown to facilitate selective translation of integrin 1 mRNA, which drives the translationally controlled assembly of a TGF receptor signaling complex containing 31 integrins, -catenin, TGF receptor I, E-cadherin and phosphorylated Smads2/3. This receptor complex acutely sensitizes non-malignant breast epithelial cells to activation by typically sub-stimulatory levels of activated TGF. TGF can promote cellular differentiation or invasion and transformation. As a translational coactivator of TGF, eIF4E confers selective mRNA translation, reprogramming non-malignant cells to an invasive phenotype by reducing the set-point for stimulation by activated TGF. Overexpression of eIF4E may be a pro-invasive facilitator of TGF activity.
Publication Title
Eukaryotic Translation Initiation Factor 4E Is a Feed-Forward Translational Coactivator of Transforming Growth Factor β Early Protransforming Events in Breast Epithelial Cells.
Sample Metadata Fields
Sex, Specimen part, Cell line
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
TREM-2 has been described to be a phagocytic receptor. We assessed the influence of TREM-2 on gene expression in alveolar macrophages (AM)
Publication Title
The triggering receptor expressed on myeloid cells 2 inhibits complement component 1q effector mechanisms and exerts detrimental effects during pneumococcal pneumonia.
Sample Metadata Fields
Specimen part
View Samples- Drosophila melanogaster
- 8 Downloadable Samples
Illumina HiSeq 2000
Description
The exon junction complex (EJC) is a highly conserved ribonucleoprotein complex which binds RNAs at a late stage of the splicing reaction and remains associated following export to the cytoplasm. This complex is involved in several cellular post-transcriptional processes including mRNA localization, translation and degradation. The EJC plays an additional role in the splicing of a subset of genes in Drosophila and in human cells but the underlying mechanism remains to be elucidated. Here, we have found a novel function for the EJC and its splicing subunit RnpS1 in preventing transposon accumulation in both Drosophila germline and surrounding follicular cells. This function is mediated specifically through the control of the splicing of the piwi transcript. In absence of RnpS1 one of the piwi intron is retained. This intron contains a weak 5’ splice site as well as degenerate transposon fragments, reminiscent of heterochromatic introns. In addition, we identified a small A/T rich region, which alters its polypyrimidine tract (PPT) and confers the RnpS1’s dependency. Finally, we showed that the removal of this intron by RnpS1 requires the initial splicing of the flanking introns, suggesting a model in which the EJC facilitates the splicing of challenging introns following its initial deposition to adjacent exon junctions. Overall design: In total there are 4 different conditions. Comparisons were made between piwi mutant vs control piwi and rnps1 KD vs controls RnpS1
Publication Title
The exon junction complex controls transposable element activity by ensuring faithful splicing of the piwi transcript.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 16 Downloadable Samples
- Illumina HiSeq 4000
Description
To gain insights into the molecular pathogenesis of DCM caused by LMNA mutation, a doxycycline-inducible (Dox-Off) gene expression system was used to express either a wild type (WT) or a mutant LMNA containing the pathogenic variant p.Asp300Asn (LMNAD300N) in cardiac myocytes. The LMNAD300N is associated with DCM in patients with atypical progeroid/Werner syndrome and non-syndromic cardiac progeria. Expression of the mutant LMNAD300N protein in cardiac myocytes led to severe fibrosis, apoptosis, cardiac dysfunction, and premature death. RNA-seq was performed (prior to onset of cardiac dysfunction) to identify gene signatures and transcriptional regulators responsible for this phenotype. Mechanistic studies identified activation of E2F/TP53/DDR, as a major mechanism responsible for the pathogenesis of DCM caused by the LMNAD300N mutation. Overall design: RNA-seq analysis from 2-week old WT and mice expressing mutant LMNA (LMNAD300N)
Publication Title
DNA Damage Response/TP53 Pathway Is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Associated With LMNA (Lamin A/C) Mutations.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 10 Downloadable Samples
- Illumina HiSeq 4000
Description
Mutations in the LMNA gene causes set of disorders collectively referred to as laminopathies that include dilated cardiomyopathy. Lamin A/C proteins a components of nuclear lamina forms distinct nuclear domains called lamina associated domains (LADs). The roles of LADs in DCM is not known. To identify LADs and characterize their associations with CpG methylation and gene expression in human cardiac myocytes isolated from patients with DCM and controls we performed Chromatin immunoprecipitation-sequencing (ChIP-Seq), reduced representative bisulfite sequencing (RRBS), and RNA-sequencing (RNA-Seq) in 5 control and 5 DCM hearts with defined pathogenic variants in the LMNA gene. LADs are redistributed in DCM, are associated with CpG methylation and suppressed transcription, contributing to the pathogenesis of DCM in laminopathies. Overall design: integrated analysis of ChIP-seq for LMNA from Cardiac myocytes and RNA-seq and RRBS from 5 control and 5 DCM human heart sample
Publication Title
Genomic Reorganization of Lamin-Associated Domains in Cardiac Myocytes Is Associated With Differential Gene Expression and DNA Methylation in Human Dilated Cardiomyopathy.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Snail1 transcriptional factor is essential for triggering epithelial-to-mesenchymal transition (EMT) and inducing tumor cell invasion. We report here that Snail1 plays also a key role in tumor associated fibroblasts since is necessary for enhancement by these cells on epithelial cells tumor invasion. Snail1 expression in fibroblast requires signals derived from tumor cells such as TGF-b; reciprocally, in fibroblasts Snail1 organizes a complex program that favors collective invasion of epithelial cells at least in part by the secretion of diffusible signaling molecules, such as prostaglandin E2. The capability of human or murine tumor-derived cancer associated fibroblasts to promote tumor invasion is associated to Snail1 expression and obliterated by Snail1 depletion. In vivo experiments show that tumor cells co-transplanted with Snail1 depleted fibroblasts show lower invasion than those xenografted with control fibroblasts. Finally Snail1 depletion in mice prevents the formation of breast tumors and decreased their invasion. Therefore, these results demonstrate that the role of Snail1 in tumor invasion is not limited to its effect in EMT but dependent on its expression in stromal fibroblasts where it orchestrates its activation and the crosstalk with epithelial cells.
Publication Title
Snail1-Dependent Activation of Cancer-Associated Fibroblast Controls Epithelial Tumor Cell Invasion and Metastasis.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 24 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Glucocorticoids (GCs) are commonly used to treat patients suffering from lymphoid malignancies i.e. leukemia and multiple myeloma. Although GCs are known to be strong inducers of apoptosis in lymphoid cells, the molecular determinants of GC therapy resistance are poorly understood. Although GC treatment triggers important changes in gene expression, few studies have addressed the regulatory role of small regulatory microRNAs (miRNAs) in GC therapy response. Only recently, aberrant microRNA expression has been linked to the development of haematological malignancies and microRNAs have become master regulators of drug resistance. We identified GC inducible mRNA and microRNA transcription profiles in GC sensitive MM1S as compared to GC resistant MM1R cells. Transcriptome analysis revealed that GCs regulate multiple genes involved in cell cycle control, cell organization and cell death in MM1S, which remain unaffected in MM1R cells. Correspondingly, GCs selectively trigger cell death in MM1S but not in MM1R. Out of 32 microRNAs responsive to GC in MM1S cells but not in MM1R cells, mir-150 was identified as the most persistent GC responsive microRNA. Furthermore, Ingenuity Pathways Analysis (IPA) revealed that ectopic transfection of a synthetic mir-150 mimics GC therapy response in MM1S cells, associated with selective changes in mRNA levels of typical GR transactivated and transrepressed target genes. Although mir-150 largely mirrors GC responsive changes in gene expression of the transcription factor Myb, GR chaperone FKBP5, cell cycle modulator proteins (IL23A, SKP2, CDKN1A), chemokine signaling proteins (CXCR4, CX3CR1, CCL3) and mTOR/UPR stress related proteins (DDIT4, TXNIP), we also observed mir-150 selective effects on transcription factors (NR3C2 (MR), Myb, Fos, Jun, C/EBP-beta, IRF4, NFE2L1, ATF3, ATF4,), chaperone molecules HSPA8, HSP90AB1), the sodium channel SCNN1G and UPR stress proteins (TRIB3, DDIT3). Remarkably, mir-150 overexpression was not able to overcome GC therapy resistance, since we could not detect GC like effects of mir-150 in GR (NR3C1) deficient MM1R cells. Altogether GC-inducible mir-150 adds a novel complex layer of regulation for fine tuning GC specific therapeutic responses in multiple myeloma.
Publication Title
Ectopic microRNA-150-5p transcription sensitizes glucocorticoid therapy response in MM1S multiple myeloma cells but fails to overcome hormone therapy resistance in MM1R cells.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the nature and dynamics of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogenous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs emerge as clinically relevant parameters in lung cancer. In this study we used an orthotopic preclinical model of lung cancer to interrogate the transcriptome of lung tumor-infiltrating DCs and extract novel biologically and clinically relevant information. Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b+ cells which, compared to peritumoral lung DC counterparts, strongly over-express the T cell inhibitory molecule PD-L1 and acquire classic markers of tumor-supporting macrophages (TAM) on their surface. Transcriptome analysis of these CD11b+ tumor-infiltrating DCs (TIDCs) indicates impaired anti-tumoral immunogenicity, confirms the skewing towards TAM-related features, and indicates exposure to a hypoxic environment. In paralled, TIDCs display a specific micro-RNA signature dominated by the prototypical lung cancer oncomir miR-31. Hypoxia was found to drive intrinsic miR-31 expression in CD11b+DCs. Conditioned medium of mir-31-overexpressing CD11b+DCs induces pro-invasive lung cancer cell shape changes and is enriched with the pro-metastatic factors S100A8 and S100A9. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer. Together, these data suggest a novel mechanism through which lung cancer co-opts the plasticity of the DC system to support tumoral progression. Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the nature and dynamics of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogenous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs emerge as clinically relevant parameters in lung cancer. In this study we used an orthotopic preclinical model of lung cancer to interrogate the transcriptome of lung tumor-infiltrating DCs and extract novel biologically and clinically relevant information. Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b+ cells which, compared to peritumoral lung DC counterparts, strongly over-express the T cell inhibitory molecule PD-L1 and acquire classic markers of tumor-supporting macrophages (TAM) on their surface. Transcriptome analysis of these CD11b+ tumor-infiltrating DCs (TIDCs) indicates impaired anti-tumoral immunogenicity, confirms the skewing towards TAM-related features, and indicates exposure to a hypoxic environment. In paralled, TIDCs display a specific micro-RNA signature dominated by the prototypical lung cancer oncomir miR-31. Hypoxia was found to drive intrinsic miR-31 expression in CD11b+DCs. Conditioned medium of mir-31-overexpressing CD11b+DCs induces pro-invasive lung cancer cell shape changes and is enriched with the pro-metastatic factors S100A8 and S100A9. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer. Together, these data suggest a novel mechanism through which lung cancer co-opts the plasticity of the DC system to support tumoral progression.
Publication Title
The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 16 Downloadable Samples
- NextSeq 500
Description
Long intergenic non-coding RNAs (lincRNAs) are emerging as integral components of signaling pathways in various cancer types. In neuroblastoma, only a handful of lincRNAs are known as upstream regulators or downstream effectors of oncogenes. Here, we exploit RNA sequencing data of primary neuroblastoma tumors, neuroblast precursor cells, neuroblastoma cell lines and various cellular perturbation model systems to define the neuroblastoma lincRNome and map lincRNAs up- and downstream of neuroblastoma driver genes MYCN, ALK and PHOX2B. Each of these driver genes controls the expression of a particular subset of lincRNAs, several of which are associated with poor survival and are differentially expressed in neuroblastoma tumors compared to neuroblasts. By integrating RNA sequencing data from both primary tumor tissue and cancer cell lines, we demonstrate that several of these lincRNAs are expressed in stromal cells. Deconvolution of primary tumor gene expression data revealed a strong association between stromal cell composition and driver gene status, resulting in differential expression of these lincRNAs. We also explored lincRNAs that putatively act upstream of neuroblastoma driver genes, either as presumed modulators of driver gene activity, or as modulators of effectors regulating driver gene expression. This analysis revealed strong associations between the neuroblastoma lincRNAs MIAT and MEG3 and MYCN and PHOX2B activity or expression. Together, our results provide a comprehensive catalogue of the neuroblastoma lincRNome, highlighting lincRNAs up- and downstream of key neuroblastoma driver genes. This catalogue forms a solid basis for further functional validation of candidate neuroblastoma lincRNAs. Overall design: CLB-GA was transduced with control or inducible shPHOX2B. The cells were treated with doxycycline for 5 days.
Publication Title
Integrative analysis identifies lincRNAs up- and downstream of neuroblastoma driver genes.
Sample Metadata Fields
Cell line, Treatment, Subject
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Characterization of differential gene expression due to cisplatin resistance in human ovarian cancer spheroids by microarray analysis.
Publication Title
Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.
Sample Metadata Fields
Specimen part, Cell line
View Samples