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GSE55170
Homo sapiens
7 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Myeloid Angiogenic Cells (MACs) were infected with the intracellular, bacterial pathogen Bartonella henselae (B.h.). Infected cells were seeded onto Matrigel coated plates. While uninfected cells showed no phenotypic changes and died over time, infected cells showed strong phenotypic changes and developed into complex 2D chord networks over the course of long term culture (eg 49d). To examine the changes in gene expression associated with the development of the B.h.dependent chord formation phenotype, RNA was isolated from MACs shortly after isolation (d4) and from cells of the chord structures (+B.h. Matrigel). As primary endothelial cells are also know to form chord networks when cultured on Matrigel, a sample of human umbilical vein endothelial cells (HUVECs) cultured on Matrigel for 12hr was also included in the analysis as a control.
Publication Title
Reprogramming of myeloid angiogenic cells by Bartonella henselae leads to microenvironmental regulation of pathological angiogenesis.
Sample Metadata Fields
Specimen part, Subject, Time
View Samples- Homo sapiens
- 12 Downloadable Samples
NextSeq 500
Description
The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) controls metabolic flux through allosteric regulation of glycolysis. Here we show that p53 regulates the expression of PFKFB4 and that p53-deficient cancer cells are highly dependent on the function of this enzyme. We found that p53 down-regulates PFKFB4 expression by binding to its promoter and mediating transcriptional repression via histone deacetylases. Depletion of PFKFB4 from p53 deficient cancer cells increased levels of the allosteric regulator fructose 2,6-bisphophate, leading to increased glycolytic activity but decreased routing of metabolites through the oxidative arm of the pentose phosphate pathway. PFKFB4 was also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53 deficient cancer cells. Moreover, depletion of PFKFB4 attenuated cellular biosynthetic activity and resulted in the accumulation of reactive oxygen species and cell death in the absence of p53. Finally, silencing of PFKFB4 induced apoptosis in p53 deficient cancer cells in vivo and interfered with tumour growth. These results demonstrate that PFKFB4 is essential to support anabolic metabolism in p53-deficient cancer cells and suggest that inhibition of PFKFB4 could be an effective strategy for cancer treatment. Overall design: Gene expression changes in HCT116 p53+/+ and p53-/- xenograft tumours after PFKFB4 silencing
Publication Title
6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for p53-null cancer cells.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 26 Downloadable Samples
- Affymetrix Human Gene 1.1 ST Array (hugene11st)
Description
Tumor-induced immunosuppression remains a major challenge for immunotherapy of cancer patients. To further elucidate why an allogeneic gene-modified (Interleukin-7(IL-7)/CD80 co-transfected) renal cell cancer vaccine failed to induce clinically relevant TH1-polarized immune responses, peripheral blood mononuclear cells (PBMCs) from enrolled study patients were analyzed by gene expression profiling (GEP) both prior and after vaccination. At baseline before vaccination, a profound downregulation of gene signatures associated with antigen presentation, immune response/T cells, cytokines/chemokines and signaling/transcription factors was observed in renal cell cancer patients as compared to healthy controls. Vaccination led to a partial reversion of preexisting immunosuppression, however, GEP indicated that an appropriate TH1 polarization could not be achieved. Most interestingly, our results suggest that the nuclear factor kappa B (NF-B) signaling pathway might be involved in the impairment of immunological responsiveness and the observed TH2 deviation. In summary, our data suggest that GEP might be a powerful tool for the prediction of immunosuppression and the monitoring of immune responses within immunotherapy trials.
Publication Title
Gene expression profiling of peripheral blood mononuclear cells during treatment with a gene-modified allogeneic tumor cell vaccine in advanced renal cell cancer: tumor-induced immunosuppression and a possible role for NF-κB.
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The branched chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. By performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem cell (LSC) and non-LSC populations, we found the BCAA pathway enriched and BCAT1 overexpressed in LSCs. We show that BCAT1, which transfers -amino groups from BCAAs to -ketoglutarate (KG), is a critical regulator of intracellular KG homeostasis. Next to its role in the tricarboxylic acid (TCA) cycle KG is an essential co-factor for KG-dependent dioxygenases such as EGLN1 and the TET family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of KG leading to HIF1a protein degradation mediated by EGLN1. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. In contrast, overexpression (OE) of BCAT1 in leukaemia cells decreased intracellular KG levels and caused DNA hypermethylation via altered TET activity. BCAT1high AMLs displayed a DNA hypermethylation phenotype similar to cases carrying mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHwtTET2wt, but not IDHmut or TET2mut AMLs. Gene sets characteristic for IDHmut AMLs were enriched in IDHwtTETwtBCAT1high patient samples. BCAT1high AMLs showed robust enrichment for LSC signatures and paired sample analysis revealed a significant increase of BCAT1 levels upon disease relapse. In summary, by limiting intracellular KG, BCAT1 links BCAA catabolism to HIF1a stability and regulation of the epigenomic landscape. Our results suggest the BCAA-BCAT1-KG pathway as a therapeutic target to compromise LSC function in IDHwtTET2wt AML patients.
Publication Title
BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation.
Sample Metadata Fields
Treatment
View Samples