Filters
Technology
Platform
GSE56031
Homo sapiens
3 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Aberrant cell proliferation, a hallmark of most cancers, requires the escape from intrinsic antitumour barriers. Primary among these is the DNA damage response (DDR). In both cell culture-models and in early stages of tumorigenesis in vivo, activated oncogenes induce DNA replication stress and DNA double-strand breaks (DSBs), leading to DDR activation and p53-dependent apoptosis and/or senescence. The means by which tumour-initiating cells, also termed cancer stem cells (CSCs), circumvent this oncosuppressive response is unknown. Here we demonstrate that the ZEB1 transcription factor provides breast CSCs with the ability to withstand an aberrant mitogenic activity. Its forced expression in human mammary epithelial cells is sufficient to alleviate DNA replicative stress and to decrease the production of reactive oxygen species, an important contributor to DDR and oncogene-induced senescence. Consistently, human breast cancer cells with endogenous ZEB1 expression show two characteristic features: low levels of DSBs and DDR markers, reflecting mitigation of the DNA replication stress, and a low p53 mutation frequency, reflecting a weak selective pressure for inactivation. Using high-throughput sequencing analysis of controlled cellular models, we further demonstrate that ZEB1 delays the onset of structural chromosomal instability (CIN), a known consequence of replicative stress and prevents the emergence of chromosome 8p deletions and 8q amplifications, two prevalent abnormalities in high-grade breast cancers. Supporting these findings, ZEB1 expression discriminates human breast tumours by their copy number alterations (CNAs) and chromosome 8 aberrations. We propose that the tumorigenic potential of CSCs relies upon their unique capacity to tolerate oncogenic stimuli through the alleviation of DNA replication stress.
Publication Title
A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
Illumina HiSeq 2500
Description
Tumours progress despite being infiltrated by effector T cells. Tumour necrosis is associated with poor survival in a variety of cancers. Here, we report that that necrosis causes release of an intracellular ion, potassium, into the extracellular fluid of human and mouse tumours. Surprisingly, elevated extracellular potassium ([K+]e) was sufficient to profoundly suppress mouse and human T cell anti-tumour function. Elevations in [K+]e acted to acutely impair T cell receptor (TCR) dependent Akt-mTOR phosphorylation and effector function. Potassium mediated suppression of Akt-mTOR signalling and T cell effector function required intact activity of PP2A, a serine/threonine phosphatase. The suppressive effect mediated by elevated [K+]e required a T cell-intrinsic increase in intracellular potassium ([K+]i) and was independent of changes in plasma membrane potential (Vm). Finally, ionic reprogramming of tumour-specific T cells via over-expression of the voltage-gated potassium channel Kv1.3 lowered [K+]i and improved effector functions in vitro and in vivo, with this gain of function being dependent on intact channel function. Consequently, Kv1.3 T cell expression enhanced tumour clearance and the survival of melanoma-bearing mice. These results uncover a previously undescribed ionic checkpoint against T cell function within tumours and identify new strategies for cancer immunotherapy. Overall design: RNA expression was measured by RNA-Seq on day 5 of cultures, maintained in individual biologial triplicates which were stimulated with immobilized anti-CD3/28 antibodies or kept in complete media (no stim) - with equivalent conditions treated with isotonic media containing elevated potassium.
Publication Title
Ionic immune suppression within the tumour microenvironment limits T cell effector function.
Sample Metadata Fields
Sex, Age, Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Continuous contact with self-major histocompatibility complex ligands is essential for the survival of naive CD4 T cells. We have previously shown that the resulting tonic TCR signaling also influences their fate upon activation by increasing their ability to differentiate into induced regulatory T cells. To decipher the molecular mechanisms governing this process, microarray data comparing highly (Ly-6C-) and lowly (Ly-6C+) Self-reactive naive CD4 T cells were obtained.
Publication Title
Calcium-mediated shaping of naive CD4 T-cell phenotype and function.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 13 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
T cell receptor (TCR) signaling is a critical process in immunity to infectious disease and cancer. Recently, a genome-wide association study has implicated polymorphisms in the CISH locus with susceptibility to infectious diseases. However, the role of Cish in the immune responses and its molecular underpinnings remains unclear. Here we demonstrate that Cish deletion resulted in protection against viral infection and enhanced CD8+ T cell tumor immunity. Transcriptome profiling revealed a hyper-TCR activation signature in Cish-deficient CD8+ T cells. Subsequent analysis revealed an inhibitory role for Cish in PLC1 activation, ensuing Ca2+ release and downstream signaling. In the steady-state Cish was found to physically interact with PLC1, however, PLC1 was only found to be ubiquitinated after acute TCR stimulation in the presence of Cish. These data implicate Cish as a potent negative regulator of TCR signaling and T cell immunity to infection and cancer and may have significant clinical applications.
Publication Title
Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 2 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidence for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Genome-wide gene expression profiling of this isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian tissues. Consistently, we observed that the proliferation of MDA-MB-231(SA) cells in serine-free conditions was dependent on PSAT1 expression. In addition, we observed that L-serine is essential for the formation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell proliferation indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions.
Publication Title
Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Gene expression data for shRNA PTPN1 knockdown vs. Non-silencing in the classical Hodgkin lymphoma-derived cell line KM-H2
Publication Title
Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
To find BMAL1-regulated genes in mice pituitary gland we performed a differential microarray from wild-type vs Bmal1-/- knock-out mice
Publication Title
Chromatin remodeling as a mechanism for circadian prolactin transcription: rhythmic NONO and SFPQ recruitment to HLTF.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
This study supports an active role for PLZF and RAR-PLZF in leukemogenesis, identifies upregulation of CRABPI as a novel mechanism contributing to retinoid resistance and reveals the ability of the reciprocal fusion gene products to mediate distinct
Publication Title
RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina HiSeq 2500
Description
De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood fatality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models,we found that Asxl1 global loss or conditional deletion in osteoblasts and their progenitors in mice leads to significant bone loss and markedly decreased numbers of marrow mesenchymal stem/progenitor cells (MSPCs) compared with wild-type (WT) littermates. Asxl1-/- MSPCs displayed impaired self-renewal and skewed differentiation-away from osteoblasts and favoring adipocytes. RNA-seq analysis reveals the altered expression of genes involved in cell proliferation, skeletal development and morphogenesis. Furthermore, gene set enrichment analysis showed a decreased gene expression of stem cell self-renewal signature,suggesting the role of Asxl1 in regulating the stemness of MSPCs. Importantly, introducing Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1-/- MSPCs. Our study unveils a pivotal role of ASXL1 in maintenance of MSPC functions and skeletal development. Overall design: Examination of mRNA profiles in wild type and Asxl1-/- MSPCs by deep sequencing
Publication Title
Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice.
Sample Metadata Fields
Specimen part, Subject
View Samples