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SRP067829
Mus musculus
7 Downloadable Samples
Illumina HiSeq 2500
Description
Tumor-associated macrophages (TAMs) have immunosuppressive capacity in mouse models of cancer. Here we show that the genetic deletion of the microRNA (miRNA)-processing enzyme DICER in TAMs broadly programs them to a CD11c+MRC1-/low M1-like immunostimulatory phenotype characterized by activated interferon-? (IFN-?)/STAT1/IRF signaling. M1-like TAM programming fostered the recruitment of cytotoxic T-cells (CTLs), including tumor-antigen-specific CTLs, inhibited tumor growth, and enhanced the efficacy of PD1 checkpoint blockade. Bioinformatics analysis of TAM transcriptomes identified a limited set of miRNAs putatively involved in TAM programming. Re-expression of Let-7 in Dicer-deficient TAMs was sufficient to partly rescue the M2-like (protumoral) TAM phenotype and abate tumor CTL infiltration. Targeted suppression of DICER activity in TAMs may, therefore, stimulate antitumor immunity and enhance the efficacy of cancer immunotherapy. Overall design: To explore the role of DICER in the development, activation and immunological functions of TAMs, we crossed homozygous LysM-Cre (Clausen et al., 1999) with Dicerlox/lox (Harfe et al., 2005) mice to obtain mice with myeloid-cell-specific Dicer1 gene deletion (LysM-Cre;Dicer–/–, referred to as D–/–). These mice were then backcrossed to LysM-Cre to obtain the control LysM-Cre; Dicer+/+ mice (referred to as D+/+). Both LysM-Cre and Dicerlox/lox mutations were always homozygous in our experiment. We then inoculated Lewis lung carcinoma (LLC) cells subcutaneously (s.c.) in D–/– and control D+/+ mice. Once the tumors were established, we isolated by fluorescence-activated cell sorting (FACS) tumor-associated macrophages (F4/80+ cells).
Publication Title
Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 24 Downloadable Samples
- IlluminaHiSeq2500
Description
Tuberous sclerosis complex (TSC) is a rare genetic disease characterized by mTOR hyperfunction induced benign tumor growths in multiple organs and neurological symptoms. Because the molecular pathology is highly complex and the etiology poorly understood we employed a defined human neuronal model with a single mTOR activating mutation to dissect the disease-relevant molecular responses driving the neuropathology. TSC2 deficient neural stem cells showed severely reduced neuronal functional maturation and characteristics of astrogliosis instead. Accordingly, transcriptome analysis uncovered an inflammatory response and increased metabolic activity, while ribosome profiling revealed excessive translation of ribosomal transcripts and higher synthesis rates of angiogenic growth factors. Treatment with mTOR inhibitors corrected translational alterations but not transcriptional dysfunction. These results extend our understanding of the molecular pathophysiology of TSC brain lesions, and suggest phenotype-tailored pharmacological treatment strategies. Overall design: Two TSC+/- cell lines and two TSC-/- cell lines were independently generated from wild-type human embryonic stem cells by genome editting with zinc finger nucleases. Two cell lines were handled in the same way but without any known human gene editted and they are used as negative controls. Two independent biological replicates of each of the six cell lines are profiled with ribosome profiling technique.
Publication Title
Genomic analysis of the molecular neuropathology of tuberous sclerosis using a human stem cell model.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Digital gene expression profiling of primary acute lymphoblastic leukemia cells.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The aim of this study was to benchmark digital gene expression (DGE) profiling by massively parallel sequencing against the most commonly used method for gene expression analysis. We compared the DGE levels to expression levels from Affymetrix arrays. Data from Affymetrix Human Genome U133 plus 2.0 GeneChips was available for 12 of the 21 RNA samples from ALL patient cells analyzed by DGE.
Publication Title
Digital gene expression profiling of primary acute lymphoblastic leukemia cells.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 30 Downloadable Samples
- IlluminaHiSeq2000
Description
The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of novel therapeutics. One promising approach has been to increase the number or activity of brown-like adipocytes in white adipose depots, as this has been shown to prevent diet-induced obesity and reduce the incidence and severity of type 2 diabetes. Thus, the conversion of fat-storing cells into metabolically active thermogenic cells has become an appealing therapeutic strategy to combat obesity. Here, we report a screening platform for the identification of small molecules capable of promoting a white-to-brown metabolic conversion in human adipocytes. We identified two inhibitors of Janus Kinase (JAK) activity with no precedent in adipose tissue biology that permanently confer brown-like metabolic activity to white adipocytes. Importantly, these metabolically converted adipocytes exhibit elevated UCP1 expression and increased mitochondrial activity. We further found that repression of interferon signalling and activation of hedgehog signalling in JAK-inactivated adipocytes contributes to the metabolic conversion observed in these cells. Our findings highlight a novel role for the JAK/STAT pathway in the control of adipocyte function and establish a platform to identify compounds for the treatment of obesity. Overall design: Human pluripotent stem-cell derived mesenchymal progenitor cells (PSC-MPCs), white adipose cells (PSC-WA), and brown adipose cells (PSC-BA) were treated with DMSO (as control), a JAK3-inhibitor compound, and a SYK-inhibitor compound respectively. Transcriptomic expression profiling was performed at 24 hours and 7 days respectively. Three biological replicates are available for each condition defined by cell type, compound, and time.
Publication Title
White-to-brown metabolic conversion of human adipocytes by JAK inhibition.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 37 Downloadable Samples
- Illumina HiSeq 4000
Description
Evidence from mouse chronic viral infection models suggests that CD8+ T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic, and functional signatures of intratumoral CD8+ T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1-) from non-small cell lung cancer patients. We observed that, PD-1T T cells show a markedly different transcriptional and metabolic profile as compared to PD-1N and PD-1- lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T lymphocytes are impaired in classical effector cytokine production, they produce CXCL13 that mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1T cells was strongly predictive for both response and survival in a small cohort of non-small cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1 bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides novel potential avenues for therapeutic intervention. Overall design: Intratumoral CD8+ T cells from 11 non-small cell lung cancer patients that were sub-sorted into PD1-high (PD-1T), PD1-intermediate (PD-1N) and PD1-negative (PD-1-) cells, were sequenced using Illumina HiSeq4000. In addition, peripheral blood effector memory T cells from 4 healthy donors were sequenced using Illumina HiSeq4000.
Publication Title
A transcriptionally and functionally distinct PD-1<sup>+</sup> CD8<sup>+</sup> T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Analysis of human iPS-derived cardiomyocytes exposed to glucose, endothelin-1 and cortisol in vitro. Treatment produces a surrogate diabetic cardiomyopathic phenotype. Results provide insight into the pathways regulated by the treatment in the cardiomyocyte.
Publication Title
Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Osteosarcoma (OS) is the malignant bone tumor with a high tendency to metastasize to the lung, where the molecular mechanisms are unclear. The mouse OS cell line LM8 has been isolated originally from the Dunn OS cell line by in vivo selection as a subline with a high metastatic potential to the lung.
Publication Title
Stable knockdown of S100A4 suppresses cell migration and metastasis of osteosarcoma.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
FIT-039 is a novel antiviral compound. Antiviral mechanism of FIT-039 is the inhibition of the viral transcription through suppression of the CTD phosphorylation of RNA polymerase II.
Publication Title
CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 4 Downloadable Samples
- IonTorrentProton
Description
We reported that NRP-1 expression on CD4+ T cells was probably induced by NRP-1 transfer from macrophages to T cells. In HER2+ BC, NRP-1 expressing TIIs correlated with better clinical outcomes. Overall design: Examination of monocytes and monocyte derived macrophages.
Publication Title
Downregulation of neuropilin-1 on macrophages modulates antibody-mediated tumoricidal activity.
Sample Metadata Fields
No sample metadata fields
View Samples