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Homo sapiens
12 Downloadable Samples
Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
We sought to obtain gene signature specific of high oxidative phsophorylation function.
Publication Title
Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
It has been hypothesized that chemotherapy resistant human acute myeloid leukemia (AML) cells are enriched in an immature phenotype, cellular quiescence and leukemic initiating cells (LICs). However, these hypotheses have never been validated completely in vivo. We have developed a physiologically relevant chemotherapeutic approach with cytosine arabinoside AraC using patient-derived xenograft (PDX) models. AraC-treated AML cells are not consistently enriched for either immature cells or quiescent cells. AraC treatment does not enrich for LICs as measured by limiting dilution in secondary transplantations. Rather chemotherapy resistant cells in vivo have high levels of reactive oxygen species (ROS) and a gene signature consistent with oxidative phosphorylation (OXPHOS). Treatment of human HIGH OXPHOS but not LOW OXPHOS AML cell lines showed chemotherapy resistance in vivo, showing that essential mitochondrial functions make significant contributions to AraC resistance in AML. Accordingly, targeting mitochondrial OXPHOS metabolism through the inhibition of mitochondrial protein synthesis, the electron transfer chain or fatty acid oxidation induced an energetic shift towards LOW OXPHOS and strongly enhanced anti-leukemic effects of AraC in AML cells. These results demonstrate that chemotherapy resistance in AML is not necessarily associated with stemness but is highly dependent on a distinct oxidative metabolism, and that the HIGH OXPHOS gene signature is a robust hallmark of the AraC response in PDX and a promising therapeutic avenue to treat AML residual disease.
Publication Title
Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism.
Sample Metadata Fields
Specimen part, Disease
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
It has been hypothesized that chemotherapy resistant human acute myeloid leukemia (AML) cells are enriched in an immature phenotype, cellular quiescence and leukemic initiating cells (LICs). However, these hypotheses have never been validated completely in vivo. We have developed a physiologically relevant chemotherapeutic approach with cytosine arabinoside AraC using patient-derived xenograft (PDX) models. AraC-treated AML cells are not consistently enriched for either immature cells or quiescent cells. AraC treatment does not enrich for LICs as measured by limiting dilution in secondary transplantations. Rather chemotherapy resistant cells in vivo have high levels of reactive oxygen species (ROS) and a gene signature consistent with oxidative phosphorylation (OXPHOS). Treatment of human HIGH OXPHOS but not LOW OXPHOS AML cell lines showed chemotherapy resistance in vivo, showing that essential mitochondrial functions make significant contributions to AraC resistance in AML. Accordingly, targeting mitochondrial OXPHOS metabolism through the inhibition of mitochondrial protein synthesis, the electron transfer chain or fatty acid oxidation induced an energetic shift towards LOW OXPHOS and strongly enhanced anti-leukemic effects of AraC in AML cells. These results demonstrate that chemotherapy resistance in AML is not necessarily associated with stemness but is highly dependent on a distinct oxidative metabolism, and that the HIGH OXPHOS gene signature is a robust hallmark of the AraC response in PDX and a promising therapeutic avenue to treat AML residual disease.
Publication Title
Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism.
Sample Metadata Fields
Specimen part, Disease, Treatment, Subject
View Samples- Homo sapiens
- 86 Downloadable Samples
- Affymetrix Human Full Length HuGeneFL Array (hu6800), Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Disparate Oxidant-related Gene Expression of Human Small Airway Epithelium Compared to Autologous Alveolar Macrophages in Response to the In Vivo Oxidant Stress of Cigarette Smoking
Publication Title
Disparate oxidant gene expression of airway epithelium compared to alveolar macrophages in smokers.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
A major limitation in the cancer treatment is the ability of cancer cells to become resistant to chemotherapeutic drugs, by multidrug establishment. Here, we evaluate the possibility to utilize MC70, either as ABC transporters inhibitor or as anticancer agent, in monotherapy or in combination with doxorubicin for cancer treatment. The study was carried out in MCF7/ADR and Caco-2, breast and colon cancer cells, respectively. Cell growth and apoptosis were measured by MTT assay and DNA laddering Elisa kit, respectively. Cell cycle perturbation and cellular targets modulation were analyzed by flowcytometry and western blotting, respectively. MC70 was analyzed for its interaction with ABC transporters, MDR-1, BCRP and MRP-1, and for its anticancer activity. In MCF7/ADR, MC70 slight inhibited cell proliferation and strongly enhanced doxorubicin effectiveness; conversely in Caco-2, it inhibited cell growth without affecting doxorubicin efficacy. In addition, it induced apoptosis, canceled in favor of necrosis when it was given in combination with high doses of the anthracycline. Moreover, MC70 inhibited cell migration probably through its residual activity as sigma-1 ligand. Among the hypothesized molecular and cellular mechanisms responsible for all these effects, modulations of cell cycle, of pAkt and of the three MAPKs phosphorylation were evidenced while activity at transcription level was excluded. MC70 can be considered as a potential new anticancer agent with the capability to enhance doxorubicin effectiveness and an interesting role in the treatment of chemotherapy resistant tumors.
Publication Title
MC70 potentiates doxorubicin efficacy in colon and breast cancer in vitro treatment.
Sample Metadata Fields
Cell line, Treatment
View Samples
SRP084282- Mus musculus
- 6 Downloadable Samples
Illumina HiSeq 2500
Description
Hepatocellular carcinoma (HCC) represents the fifth most common form of cancer worldwide and carries a high mortality rate due to lack of effective treatment. Males are eight times more likely to develop HCC that females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28, a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver, with Trim28hep-/- mice displaying sex-specific transcriptional deregulation of a wide range of bile and steroid metabolism genes and development of liver adenomas in males. We now demonstrate that obesity and ageing precipitate alterations of TRIM28-dependent transcriptional dynamics, leading to a metabolic infection state responsible for highly penetrant male-restricted hepatic carcinogenesis. Molecular analyses implicate aberrant androgen receptor stimulation, biliary acid disturbances and altered responses to gut microbiota in the pathogenesis of Trim28hep-/--associated HCC. Correspondingly, androgen deprivation markedly attenuates the frequency and severity of tumors, and raising animals under axenic conditions completely abrogates their abnormal phenotype, even upon high-fat diet challenge. This work underpins how discrete polyphenic traits in epigenetically unstable conditions can contribute to a cancer-prone state, and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota and cancer. Overall design: Transcriptome profiling of liver tissues from TgAlbCre or TgAlbCreKap1lox mice in HFD settings
Publication Title
Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice.
Sample Metadata Fields
Specimen part, Subject, Time
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Gene transfer into HSCs by gammaretroviral vectors (RV) is an effective treatment for inherited blood disorders, although potentially limited by the risk of insertional mutagenesis. We evaluated the genomic impact of RV integration in T-lymphocytes from adenosine deaminase (ADA)-Severe combined immunodeficiency (SCID) patients 10 to 30 months after infusion of autologous, genetically-corrected CD34+ cells. Expression profiling on ex vivo T-cell bulk population revealed no difference with respect to healthy controls. To assess the effect of vector integration on gene expression at the single cell level, primary T-cell clones were isolated from two patients. T-cell clones harboured either one or two vector copies per cell and displayed partial to full correction of ADA expression, purine metabolism and TCR-driven functions. Analysis of retroviral integration sites (RIS) indicated a high diversity in T-cell origin, consistent with the polyclonal TCR-Vbeta repertoire. Quantitative transcript analysis of 120 genes within a 200kb-window around RIS showed modest (2.8- to 5.2-fold) disregulation of 5.8% genes in 18.6% of the T-cell clones compared to controls. Nonetheless, affected clones maintained a stable phenotype and normal functions in vitro. These results confirm that RV-mediated gene transfer for ADA-SCID is safe, and provide crucial information for the development of future gene therapy protocols.
Publication Title
Integration of retroviral vectors induces minor changes in the transcriptional activity of T cells from ADA-SCID patients treated with gene therapy.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 28 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Microarray was used to identify differential gene expression pattern in Barrett's esophagus (BE), compared to the normal adjacent epithelia gastric cardia (GC) and normal squamous esophagus (NE)
Publication Title
Evidence for a functional role of epigenetically regulated midcluster HOXB genes in the development of Barrett esophagus.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus, Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
To elucidate mechanisms of cancer progression, we generated inducible human neoplasia in 3-dimensionally intact epithelial tissue. Gene expression profiling of both epithelia and stroma at specific time points during tumor progression revealed sequential enrichment of genes mediating discrete biologic functions in each tissue compartment. A core cancer progression signature was distilled using the increased signaling specificity of downstream oncogene effectors and subjected to network modeling. Network topology predicted that tumor development depends upon specific ECM-interacting network hubs. Blockade of one such hub, the b1 integrin subunit, disrupted network gene expression and attenuated tumorigenesis in vivo. Thus, integrating network modeling and temporal gene expression analysis of inducible human neoplasia provides an approach to prioritize and characterize genes functioning in cancer progression.
Publication Title
Modeling inducible human tissue neoplasia identifies an extracellular matrix interaction network involved in cancer progression.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 5 Downloadable Samples
- Illumina HiSeq 2000
Description
Huntington neurodegenerative disease (HD) is associated with extensive down-regulation of neuronal genes. We show preferential down-regulation of super-enhancer-regulated neuronal function genes in the striatum of HD mice. Striatal super-enhancers display extensive H3K27 acetylation within gene bodies and drive transcription characterized by low levels of paused RNAPII. Down-regulation of gene expression is associated with diminished H3K27 acetylation and RNAPII recruitment. Striatal super-enhancers are enriched in binding motifs for Gata transcription factors, such as Gata2 regulating striatal identity genes. Thus, enhancer topography and transcription dynamics are major parameters determining the propensity of a gene to be deregulated in a neurodegenerative disease. Overall design: RNA profiles in Striatum of WT and R6/1 mice by deep sequencing using Illumina HiSeq 2000.
Publication Title
Altered enhancer transcription underlies Huntington's disease striatal transcriptional signature.
Sample Metadata Fields
No sample metadata fields
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