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GSE89395
Mus musculus
8 Downloadable Samples
Affymetrix Mouse Gene 2.1 ST Array (mogene21st)
Description
Resistance towards anti-angiogenic therapy (AAT) still represents a substantial clinical challenge. We report here that tumor-infiltrating mast cells (MC) are powerful mediators decreasing efficacy of AAT in mice and cancer patients. They act in a cell-extrinsic manner by secreting granzyme B, which liberates pro-angiogenic mediators from the extracellular matrix. In addition, MC also diminish efficacy of anti-angiogenic agents in a cell-autonomous way, which can be blocked by the mast cell degranulation inhibitor cromolyn. Our findings are relevant in humans because patients harboring higher numbers of MC in their tumors have an inferior outcome after anti-angiogenic treatment in the Gepar Quinto randomized Phase 3 clinical trial. Thus, MC-targeting might represent a novel promising approach to increase efficacy of AAT.
Publication Title
Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
Illumina HiSeq 3000
Description
Effector (Teff) and regulatory (Treg) CD4 T cells undergo metabolic reprogramming to support proliferation and immune function. While Phosphatidylinositide 3-kinase (PI3K)/Akt/mTORC1 signaling induces the glucose transporter Glut1 and aerobic glycolysis for Teff proliferation and inflammatory function, mechanisms that regulate Treg metabolism and function remain unclear. We show that TLR signals that promote Treg proliferation increase Glut1, PI3K/Akt/mTORC1 signaling, and glycolysis. However, TLR-induced mTORC1 signaling also impaired Treg suppressive capacity. Conversely, FoxP3 opposed PI3K/Akt/mTOR signaling to reduce glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Importantly, Glut1 expression was sufficient to increase Treg numbers but reduced suppressive capacity and FoxP3 expression. Thus, inflammatory signals and FoxP3 balance mTORC1 signaling and glucose metabolism to control Treg proliferation and suppressive function. Overall design: RNAseq of induced Glut1 transgenic and control Treg
Publication Title
Foxp3 and Toll-like receptor signaling balance T<sub>reg</sub> cell anabolic metabolism for suppression.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 3000
Description
Activated T cells differentiate into functional subsets which require distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to provide substrate for the tricarboxylic acid cycle and epigenetic reactions and here we identify a key role for GLS in T cell activation and specification. Though GLS-deficiency diminished T cell activation, proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet and Interferon-? expression and CD4 Th1 and CD8 CTL effector cell differentiation. These changes were mediated by differentially altered gene expression and chromatin accessibility, leading to increased sensitivity of Th1 cells to IL-2 mediated mTORC1 signaling. In vivo, GLS-null T cells failed to drive a Th17-mediated Graft-vs-Host Disease model. Transient inhibition of GLS, however, increased Th1 and CTL T cell numbers in viral and chimeric antigen receptor models. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation. Overall design: Cells were treated with glutaminase1 inhibitor or vehicle
Publication Title
Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 15 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Previously published data suggested some redundant functions between HDAC1 and HDAC2 in mouse. To test this hypothesis, we used microarrays to have a genome wide analysis at the transcription level of primary MEFs lacking HDAC1, HDAC2.
Publication Title
Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Hepatic fibrosis is a wound-healing response to chronic liver injury, which may result in cirrhosis and liver failure. The c-Jun N-terminal kinase-1 (JNK1) gene has been shown to be involved in liver fibrosis. Here, we aimed to investigate the molecular mechanism and identify the cell-type involved in mediating the JNK1-dependent effect on liver fibrogenesis Wild-type (WT), JNK1/ and JNK1hepa (hepatocyte-specific deletion of JNK1) mice were subjected to bile duct ligation (BDL). Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs) and studied their activation in vitro. Serum markers of liver damage (liver transaminases, alkaline phosphatase and bilirubin) and liver histology revealed reduced injury in JNK1/ compared to WT and JNK1hepa mice. Hepatocyte cell death and proliferation was reduced in JNK1/ compared to WT and JNK1hepa. Parameters of liver fibrosis such as Sirius Red staining as well as Collagen IA1 and SMA expression were down-regulated in JNK1/ compared to WT and JNK1hepa livers, 4 weeks after BDL. To delineate the essential cell-type, we performed BMT of WT and JNK1-/- into JNK1-/- and WT mice, respectively. BMT experiments excluded bone marrow derived cells from having a major impact on the JNK1-dependent effect on fibrogenesis. Hence, we investigated primary HSCs from JNK1/ livers showing reduced transdifferentiation compared with WT and JNK1hepa-derived HSCs. We conclude that JNK1 in HSCs plays a crucial role in hepatic fibrogenesis and thus represents a promising target for cell-directed treatment options for liver fibrosis.
Publication Title
Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment, Time
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury and cancer. Deletion of NF-B essential modulator in hepatocytes (Nemohepa) causes the spontaneous development of hepatocellular carcinoma preceded by steatohepatitis in mice and thus serves as an excellent model for the progression from chronic hepatitis to liver cancer. In the present study we aimed to dissect the death-receptor mediated pathways that contribute to liver injury in Nemohepa mice. Therefore, we generated Nemohepa/TRAIL-/- and Nemohepa/TNFR1-/- animals and analyzed the progression of liver injury. Nemohepa/TRAIL-/- displayed a similar phenotype to Nemohepa mice characteristic of high apoptosis, infiltration of immune cells, hepatocyte proliferation and steatohepatitis. These pathophysiological features were significantly ameliorated in Nemohepa/TNFR1-/- livers. Hepatocyte apoptosis was increased in Nemohepa and Nemohepa/TRAIL-/- mice while Nemohepa/TNFR1-/- animals showed reduced cell death concomitant with a strong reduction in pJNK levels. Cell cycle parameters were significantly less activated in Nemohepa/TNFR1-/- livers. Additionally, markers of liver fibrosis and indicators of tumour progression were significantly decreased in these animals. The present data demonstrate that the death receptor TNFR1 but not TRAIL is important in determining progression of liver injury in hepatocyte-specific Nemo knockout mice.
Publication Title
TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Aberrant biliary hyperproliferation resulting from lack of differentiating signals favoring the maintenance of an immature and proliferative phenotype by biliary epithelial cells are ultimately responsible for ducto/cystogenesis and intrahepatic cholangiocarcinoma (CCA) formation. Mitogen-activated protein kinase (MAPK) signaling is pivotal for CCA-related tumorigenesis. In particular, targeted inhibition of JNK signaling has shown therapeutic potential. However, the cell-type specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remains largely unknown. Here, we aimed to investigate the relevance of JNK function in hepatocytes in experimental carcinogenesis. JNK signaling in hepatocytes was inhibited by crossing AlbCre-JNK1LoxP/LoxP mice with JNK2-deficient mice to generate Jnk1LoxP/LoxP/Jnk2−/− (JNKΔhepa) mice. JNKΔhepa mice were further interbred with hepatocyte-specific Nemo-knockout mice (NEMOΔhepa), a model of chronic liver inflammation and spontaneous hepatocarcinogenesis, to generate NEMO/JNKΔhepa mice. The impact of JNK deletion on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development in NEMOΔhepa mice was determined. Moreover, regulation of essential genes was assessed by RT-PCR, immunoblottings and immunostains. Additionally, JNK2 inhibition, specifically in hepatocytes of NEMOΔhepa/JNK1Δhepa mice, was performed using siRNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of JNK1 and JNK2 in hepatocytes diminished hepatocarcinogenesis in both the DEN model of hepatocarcinogenesis and in NEMOΔhepa mice, but, in contrast, caused massive proliferation of the biliary ducts. Indeed, JNK deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression, but reduced hepatocarcinogenesis. Furthermore, siJnk2 treatment in NEMOΔhepa/JNK1Δhepa mice recapitulated the phenotype of NEMOΔhepa/JNKΔhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMOΔhepa mice. We found that NEMOΔhepa/JNKΔhepa livers exhibited overexpression of the IL-6/Stat3 pathway in addition to EGFR-Raf-MEK-ERK cascade. The functional relevance was tested by administering lapatinib - a dual tyrosine kinase inhibitor (TKI) of ErbB2 and EGFR signaling - to NEMOΔhepa/JNKΔhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases and effectively blocked EGFR-Raf-MEK-ERK signaling. Our study defines a novel function of JNK in cell fate as well as hepatocarcinogenesis and opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.
Publication Title
Loss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma.
Sample Metadata Fields
Age, Specimen part, Treatment
View Samples- Homo sapiens
- 7 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [probe set (exon) version (huex10st)
Description
Recent advances in high density oligonucleotides microarray technology have brought solutions for molecular profiling of human samples at an unprecedented resolution. We mapped whole blood RNA from healthy volunteers and CD34+ from cytapheresis to Human Exon ST 1.0 microarrays. We compared mature blood cells samples with immature CD34+ samples and each of these compartiement with a broad panel of solid tissues. By scanning the expression of over one million known or predicted exons, transcripts such as INPP4B, NEDD9 CD74 and VAV3 were identified as alternatively transcribed between haematopoietic system and solid tissues. The very large combinatorial complexity conveyed by alternative splicing contributes to the specific functional properties of blood cells and haematopoietic stem cells. The gene expression profiles are freely accessible through a dynamic web atlas, providing to the medical and scientific community a simple mean to interrogate and visualize this reference dataset. Finally, the relevance and the precision provided by this exon expression map suggest that exon arrays may be a powerful tool to link specific peripheral whole blood exon signatures modifications to many diseases such as cancer or auto-immune disorders.
Publication Title
Expression map of the human exome in CD34+ cells and blood cells: increased alternative splicing in cell motility and immune response genes.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
LMO2 regulates gene expression facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the Germinal Center (GC) reaction and is expressed in GC-derived non-Hodgkins lymphomas. LMO2 is one of the most powerful prognostic indicators in DLBCL patients. However, its function in GC B cells and DLBCL is currently unknown. In the present study we characterized the LMO2 transcriptome and interactome in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners such as LDB1, E2A, HEB, Lyl1, ETO2 and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, NFATc1 and LEF-1 proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF-1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provide a platform for future elucidation of LMO2 function in GC B-cells and DLBCL pathogenesis.
Publication Title
Identification of LMO2 transcriptome and interactome in diffuse large B-cell lymphoma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
ID8-based ovarian tumors were developed for 3 weeks in wild type (WT, N=3) or conditional knockout mice selectively deleting XBP1 in CD11c positive cells (KO, N=3). Tumor-associated DCs were independently sorted via FACS and used for transcriptional profiling. Overall design: Total RNA from sorted tumor-associated DCs (N=3/genotype) was independently isolated using the miRVANA kit (Life Technologies) and further purified and concentrated using minElute columns (Qiagen). RNA integrity was confirmed using an Agilent Bioanalyzer 2100.
Publication Title
ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.
Sample Metadata Fields
No sample metadata fields
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