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GSE71939
Homo sapiens
16 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The aim of the study was to evaluate cocaine-induced changes in gene expression in a dopaminergic model.
Publication Title
Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 61 Downloadable Samples
Illumina HiSeq 2000
Description
Panel of 53 melanoma cell lines were gene expression profiled by RNA-Seq for molecular classification Overall design: mRNA profiles of 53 melanoma cell lines
Publication Title
Interleukin 32 expression in human melanoma.
Sample Metadata Fields
Disease, Disease stage, Cell line, Subject
View Samples- Homo sapiens
- 4 Downloadable Samples
- Illumina HiSeq 2000, Affymetrix Human Gene 2.1 ST Array (hugene21st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 169 Downloadable Samples
- IlluminaHiSeq2000
Description
Melanoma resistance to MAPK- or T cell checkpoint-targeted therapies represents a major clinical challenge, and treatment failures of MAPK-targeted therapies due to acquired resistance often require salvage immunotherapies. We show that genomic analysis of acquired resistance to MAPK inhibitors revealed key driver genes but failedto adequately account for clinical resistance. From a large-scale comparative analysis of temporal transcriptomes from patient-matched tumor biopsies, we discovered highly recurrent differential expression and signature outputs of c-MET, LEF1 and YAP1 as drivers of acquired MAPK inhibitor resistance. Moreover, integration of gene- and signature-based transcriptomic analysis revealed profound CD8 T cell deficiency detected in half of resistant melanomas in association with downregulation of dendritic cells and antigen presentation. We also propose a major methylomic basis to transcriptomic evolution under MAPK inhibitor selection. Thus, this database provides a rich informational resource, and the current landscape represents a benchmark to understanding melanoma therapeutic resistance. Overall design: Melanoma biopsies pre and post MAPKi treatment were sent for RNAseq analysis
Publication Title
Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 13 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The first clinical trial testing the combination of targeted therapy with a BRAF inhibitor vemurafenib and immunotherapy with a CTLA-4 antibody ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of the MAPK pathway by BRAF inhibitors in tumors with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while potentially alleviating the unwanted paradoxical MAPK activation. With a mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of the MEK inhibitor trametinib would enhance the immunosensitization effects of the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression. Bioluminescent imaging and tumor infiltrating lymphocyte (TIL) phenotyping showed increased effector infiltration to tumors with dabrafenib, trametinib or dabrafenib plus trametinib with pmel-1 ACT combination. Intracellular IFN gamma staining of the TILs and in vivo cytotoxicity studies showed trametinib was not detrimental to the effector functions in vivo. Dabrafenib increased tumor associated macrophages and T regulatory cells (Tregs) in the tumors, which can be overcome by addition of trametinib. Microarray analysis revealed increased melanoma antigen, MHC expression, and global immune-related gene upregulation with the triple combination therapy. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen specific ACT, we tested the triple combination of dabrafenib, trametinib with anti-PD1 therapy, and observed superior anti-tumor effect to SM1 tumors. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma.
Publication Title
Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.
Sample Metadata Fields
Specimen part, Treatment, Compound
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Gene 2.1 ST Array (hugene21st)
Description
Melanoma resistance to MAPK- or T cell checkpoint-targeted therapies represents a major clinical challenge, and treatment failures of MAPK-targeted therapies due to acquired resistance often require salvage immunotherapies. We show that genomic analysis of acquired resistance to MAPK inhibitors revealed key driver genes but failedto adequately account for clinical resistance. From a large-scale comparative analysis of temporal transcriptomes from patient-matched tumor biopsies, we discovered highly recurrent differential expression and signature outputs of c-MET, LEF1 and YAP1 as drivers of acquired MAPK inhibitor resistance. Moreover, integration of gene- and signature-based transcriptomic analysis revealed profound CD8 T cell deficiency detected in half of resistant melanomas in association with downregulation of dendritic cells and antigen presentation. We also propose a major methylomic basis to transcriptomic evolution under MAPK inhibitor selection. Thus, this database provides a rich informational resource, and the current landscape represents a benchmark to understanding melanoma therapeutic resistance.
Publication Title
Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Background: Gq-coupled G protein-coupled receptors (GPCR) mediate the actions of a variety of messengers that are key regulators of cardiovascular function. Enhanced Gaq-mediated signaling plays an important role in cardiac hypertrophy and in the transition to heart failure. We have recently described that Gaq acts as an adaptor protein that facilitates PKCz-mediated activation of ERK5 in epithelial cells. Since the ERK5 cascade is known to be involved in cardiac hypertrophy, we have investigated the potential relevance of this pathway in Gq-dependent signaling in cardiac cells.
Publication Title
Protein kinase C (PKC)ζ-mediated Gαq stimulation of ERK5 protein pathway in cardiomyocytes and cardiac fibroblasts.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 22 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Differential gene expression analysis of parental and resistant sub-lines of melanoma cell lines treated or untreated with PLX4032
Publication Title
Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus, Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Recurrent Tumor Cell-Intrinsic and -Extrinsic Alterations during MAPKi-Induced Melanoma Regression and Early Adaptation.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 39 Downloadable Samples
- IlluminaHiSeq2000
Description
Treatment of advanced V600BRAF mutant melanoma using a BRAF inhibitor (BRAFi) or its combination with a MEKi typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPKi therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell-intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or -positive fractions,, implying tumor cell-intrinsic or stromal/immune alterations, respectively). Tumor cell-intrinsic reprogramming attenuated MAPK-dependency, while enhancing mesenchymal, angiogenic and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c+ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations. Overall design: Paired melanoma biopsies/cell lines before treatment, during treatment and after resistance to MAPKi were sent for transcriptomic analysis by paired end 2x100bp HiSeq 2000 RNAseq analysis
Publication Title
Recurrent Tumor Cell-Intrinsic and -Extrinsic Alterations during MAPKi-Induced Melanoma Regression and Early Adaptation.
Sample Metadata Fields
No sample metadata fields
View Samples