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SRP104686
Mus musculus
192 Downloadable Samples
NextSeq 500
Description
Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T cell activation and improved function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for treatment of NSCLC. Overall design: Single-cell comparison of vehicle (control) and HDAC inhibitor (ricolinostat)-treated tumor infiltrating T cells and macrophages
Publication Title
Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 87 Downloadable Samples
- Illumina HiSeq 2000
Description
Large-scale genomic profiling efforts have facilitated the characterization of molecular alterations in cancers and aided the development of targeted kinase inhibitors for a wide array of cancer types. However, resistance to these targeted therapies invariably develops and limits their clinical efficacy. Targeting tumours with kinase inhibitors induces complex adaptive survival programs that promote the persistence of a fraction of the original cancer cell population, facilitating the eventual outgrowth of inhibitor-resistant tumour clones following clonal evolution. Here we show that the addition of a newly identified transcriptional repressor, THZ1, to targeted cancer therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in cellular and in vivo cancer models with diverse genetic dependencies. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant. THZ1 can exploit this dependency by blocking dynamic transcriptional responses, remodelling of enhancers and key signalling outputs required for tumour cell survival in the setting of targeted cancer therapies. These findings suggest that the addition of THZ1 to targeted cancer therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations. Overall design: RNA-seq in tumor cell lines treated with targeted therapies and/or transcriptional inhibitors
Publication Title
Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression.
Sample Metadata Fields
Specimen part, Cell line, Subject, Compound
View Samples- Homo sapiens
- 2 Downloadable Samples
Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Evaluation of the genome wide impact of PARPi gene expression programs
Publication Title
PARP-1 regulates DNA repair factor availability.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used microarrays to detail the global programme of gene expression by circulating TCRVgamma9+ gamma delta T cells isolated from healthy individuals,tested either as resting cells or cells activated by phosphoantigen BrHPP and IL-2at an early(+6hrs) and a late (+7days) timepoint.
Publication Title
The gene expression profile of phosphoantigen-specific human γδ T lymphocytes is a blend of αβ T-cell and NK-cell signatures.
Sample Metadata Fields
Specimen part, Disease, Treatment, Subject, Time
View Samples- Danio rerio
- 12 Downloadable Samples
- Affymetrix Zebrafish Genome Array (zebrafish)
Description
Differentially expressed genes along the paraxial mesoderm of 12 somite stage zebrafish embryos are identified
Publication Title
Spatiotemporal compartmentalization of key physiological processes during muscle precursor differentiation.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
We have previously shown that Heparin (Hep) significantly inhibited Enterovirus 71 (EV71) infection and binding in both Vero and a human neural cell line, SK-N-SH, in vitro. Therefore, in this study we intended to gain insight into the cellular and molecular mechanisms of action of Hep against clinical EV71 infection in neural cells. Instead of stating a long list of gene functions and pathways, we tried to select for EV71-induced genes that were exclusively affected by antiviral activity of Hep through a multi-level comparison and characterization.
Publication Title
Global impact of heparin on gene expression profiles in neural cells infected by enterovirus 71.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 2 Downloadable Samples
- Illumina HiSeq 2000
Description
To try to identify the mechanism of STAT3s indirect action we have used a genomic approach to map the binding sites of STAT3 within the genome and also used RNA-seq technology to map the changes in RNA expression and transcript isoform abundance in response to IL-10. Overall design: Examination of transcriptome changes in peritoneal macrophages when treated with IL-10 for 4 hours. RNA was extracted and sequenced.
Publication Title
Genome-wide analysis of STAT3 binding in vivo predicts effectors of the anti-inflammatory response in macrophages.
Sample Metadata Fields
Sex, Specimen part, Cell line, Subject
View Samples- Mus musculus
- 2 Downloadable Samples
- Illumina HiSeq 2000
Description
RNA-seq was used to look at the transcriptome changes and the early events of T cell receptor stimulation in CD4+ T cells Overall design: CD4+ T cells were stimulated with immobilised anti-CD3/CD28 antibodies for 4 hours and RNA was extracted and subjected to RNA-seq analysis.
Publication Title
Discovery and characterization of new transcripts from RNA-seq data in mouse CD4(+) T cells.
Sample Metadata Fields
Sex, Specimen part, Cell line, Treatment, Subject
View Samples- Arabidopsis thaliana
- 9 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
Plant growth promoting rhizobacteria (PGPR) induce positive effects in plants, such as increased growth or reduced stress susceptibility. The mechanisms behind PGPR/plant interaction are poorly understood, as most studies have described short- term responses on plants and only a few studies have analyzed plant molecular responses under PGPR colonization.
Publication Title
Effects of the plant growth-promoting bacterium Burkholderia phytofirmans PsJN throughout the life cycle of Arabidopsis thaliana.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 16 Downloadable Samples
- Illumina MouseRef-8 v2.0 expression beadchip
Description
Effective immune responses depend upon appropriate T cell differentiation in accord with the nature of an infectious agent, and the contingency of differentiation depends minimally on T cell antigen receptor, co-receptor, and cytokine signals. In this reverse genetic study we show that the Map Kinase, Erk2, is nonessential for T cell proliferation in the presence of optimum co-stimulation. Instead, it has opposite polar effects on T-bet and Gata3 expression and hence on Th1 and Th2 differentiation. Alternatively, in the presence of TGFbeta, the Erk pathway suppresses a large program of gene expression effectively limiting the differentiation of Foxp3+ T reg cells. In the latter case, the mechanisms involved include suppression of Gata3 and Foxp3, induction of Tbx21, phosphorylation of Smad2,3, and possibly suppression of Socs2, a positive inducer of Stat5 signaling. Consequently, loss of Erk2 severely impeded Th1 differentiation while enhancing the development of Foxp3+ induced T regulatory cells. Selected profiles of gene expression under multiple conditions of T cell activation illustrate the opposing consequences of Erk pathway signaling.
Publication Title
Polar opposites: Erk direction of CD4 T cell subsets.
Sample Metadata Fields
Specimen part, Time
View Samples