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GSE26910
Homo sapiens
21 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Primary tumor growth induces host tissue responses that are believed to support and promote tumor progression. Identification of the molecular characteristics of the tumor microenvironment and elucidation of its crosstalk with tumor cells may therefore be crucial for improving our understanding of the processes implicated in cancer progression, identifying potential therapeutic targets, and uncovering stromal gene expression signatures that may predict clinical outcome. A key issue to resolve, therefore, is whether the stromal response to tumor growth is largely a generic phenomenon, irrespective of the tumor type, or whether the response reflects tumor-specific properties. To address similarity or distinction of stromal gene expression changes during cancer progression, oligonucleotide-based Affymetrix microarray technology was used to compare the transcriptomes of laser-microdissected stromal cells derived from invasive human breast and prostate carcinoma. Invasive breast and prostate cancer-associated stroma was observed to display distinct transcriptomes, with a limited number of shared genes. Interestingly, both breast and prostate tumor-specific dysregulated stromal genes were observed to cluster breast and prostate cancer patients, respectively, into two distinct groups with statistically different clinical outcomes. By contrast, a gene signature that was common to the reactive stroma of both tumor types did not have survival predictive value. Univariate Cox analysis identified genes whose expression level was most strongly associated with patient survival. Taken together, these observations suggest that the tumor microenvironment displays distinct features according to the tumor type that provides survival-predictive value.
Publication Title
Identification of prognostic molecular features in the reactive stroma of human breast and prostate cancer.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Metastasis depends on the ability of tumor cells to establish a relationship with the newly seeded host tissue that is conducive to their survival and proliferation. Recent evidence suggests that tumor cells regulate their own dissemination by preparing permissive metastatic niches within host tissues. However, the factors that are implicated in rendering tissues permissive for metastatic tumor growth have yet to be fully elucidated. Breast tumors arising during pregnancy display highly aggressive behaviour and early metastatic proclivity, raising the possibility that pregnancy may constitute a physiological condition of permissiveness for tumor dissemination. We show that during murine gestation, both the rate and degree of metastatic tumor growth are enhanced irrespective of tumor type and that decreased natural killer (NK) cell activity is responsible for the observed increase in experimental metastasis. We identify gene expression changes in pregnant mouse lung and liver that bear striking similarity with reported pre-metastatic niche signatures and several of the up-regulated genes are indicative of myeloid-cell infiltration. We provide evidence, that CD11b+ Gr-1+ myeloid-derived suppressor cells accumulate in pregnant mice and exert an inhibitory effect on NK cell activity, thereby enhancing metastatic tumor growth. MDSC have never been evoked in the context of pregnancy and our observations suggest that they may represent a further shared mechanism of immune suppression occurring during gestation and tumor growth.
Publication Title
Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Expression of the SS18/SYT-SSX fusion protein is believed to underlie the pathogenesis of synovial sarcoma (SS). Recent evidence suggests that deregulation of the Wnt pathway may play an important role in SS but the mechanisms whereby SS18-SSX might affect Wnt signaling remain to be elucidated. Here, we show that SS18/SSX tightly regulates the elevated expression of the key Wnt target AXIN2 in primary SS. SS18-SSX is shown to interact with TCF/LEF, TLE and HDAC but not -catenin in vivo and to induce Wnt target gene expression by forming a complex containing promoter-bound TCF/LEF and HDAC but lacking -catenin. Our observations provide a tumor-specific mechanistic basis for Wnt target gene induction in SS that can occur in the absence of Wnt ligand stimulation.
Publication Title
The fusion protein SS18-SSX1 employs core Wnt pathway transcription factors to induce a partial Wnt signature in synovial sarcoma.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Lung cancer is a highly malignant tumor and the majority of cancer-related deaths are due to metastasis. The tumor microenvironment (TME) plays a fundamental role in the metastatic spread of tumor cells. Among other stromal cells, mesenchymal stem cells (MSCs) are known to be present within the TME and to be involved in cancer progression. However the majority of previous studies have been performed on bone marrow-derived MSCs. To investigate the role of the TME on the pulmonary MSC phenotype, we compared the expression profile of paired MSCs isolated from lung tumor (T-) and normal adjacent tissues (N-) from lung carcinoma patients.
Publication Title
Reciprocal modulation of mesenchymal stem cells and tumor cells promotes lung cancer metastasis.
Sample Metadata Fields
Specimen part, Disease stage, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Overexpression of the Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2) occurs in diverse malignancies, including prostate cancer, breast cancer, and glioblastoma multiforme (GBM) (1). Based on its ability to modulate transcription of key genes implicated in cell cycle control, DNA repair and cell differentiation, EZH2 is believed to play a crucial role in tissue-specific stem cell maintenance and tumor development. Here we show that targeted pharmacologic disruption of EZH2 by the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A (DZNep), or its specific down-regulation by shRNA, strongly impairs GBM cancer stem cell self-renewal in vitro and tumor-initiating capacity in vivo. Using genome-wide expression analysis of DZNep-treated GBM cancer stem cells, we found the expression of c-myc, recently reported to be essential for GBM cancer stem cells, to be strongly repressed upon EZH2 depletion. Specific shRNA-mediated down-regulation of EZH2 in combination with chromatin immunoprecipitation (ChIP) experiments revealed that c-myc is a direct target of EZH2 in GBM cancer stem cells. Taken together, our observations provide evidence that direct transcriptional regulation of c-myc by EZH2 may constitute a novel mechanism underlying GBM cancer stem cell maintenance and suggest that EZH2 may be a valuable new therapeutic target for GBM management.
Publication Title
EZH2 is essential for glioblastoma cancer stem cell maintenance.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Cancer stem cells (CSCs) display plasticity and self-renewal properties reminiscent of normal tissue stem cells, but the events responsible for their emergence remain obscure. We recently identified CSCs in Ewing sarcoma family tumors (ESFTs) and showed that they retain mesenchymal stem cell (MSC) plasticity. In the present study, we addressed the mechanisms that underlie ESFT CSC development. We show that the EWS-FLI-1 fusion gene, associated with 85%-90% of ESFTs and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2, and NANOG in human pediatric MSCs (hpMSCs) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSCs expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWS-FLI-1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene, SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a CSC phenotype.
Publication Title
EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
IlluminaHiSeq2000
Description
We show that EWS-FLI1, an aberrant transcription factor responsible for the pathogenesis of Ewing sarcoma, reprograms gene regulatory circuits by directly inducing or directly repressing enhancers. At GGAA repeats, which lack regulatory potential in other cell types and are not evolutionarily conserved, EWS- FLI1 multimers potently induce chromatin opening, recruit p300 and WDR5, and create de novo enhancers. GGAA repeat enhancers can loop to physically interact with target promoters, as demonstrated by chromosome conformation capture assays. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors and abrogating p300 recruitment. Overall design: Ewing sarcoma cell lines (A673 and SKNMC) were analyzed by RNA-seq. EWS-FLI1 was depleted by infection with lentiviral shRNAs (shFLI1 and shGFP control).
Publication Title
EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Proteomic analysis of Medulloblastoma reveals functional biology with translational potential.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
These gene expression microarrays were performed as part of a project aiming to integrate quantitative proteomic, gene expression and epigenetic data from the childhood brain tumor medulloblastoma.
Publication Title
Proteomic analysis of Medulloblastoma reveals functional biology with translational potential.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 22 Downloadable Samples
Description
Cancer evolution is fueled by genetic and epigenetic diversity, and intra-tumoral heterogeneity in DNA methylation has been shown to co-operate with genetic heterogeneity to empower evolutionary capacity of cancers such as chronic lymphocytic leukemia. Here, we show that epigenetic diversification leads to decreased coordination across layers of epigenetic information, likely reflecting an admixture of cells with diverging epigenetic identities. This manifests in incomplete gene silencing by the Polycomb complex, unexpected co-occurrence of typically mutually exclusive activating and repressing histone modifications, and greater cell-to-cell transcriptional heterogeneity. Overall design: Given the importance of histone modifications to lineage plasticity in cancer15-17, intra-leukemic epigenetic heterogeneity may extend to histone modifications, likely promoting lineage plasticity by enabling permissive chromatin states. To address this question, we complemented DNAme analysis with a chromatin immunoprecipitation sequencing (ChIP-seq) compendium of histone post-translational modifications (H3K4me3, H3K27ac, H3K4me1, H3K27me3, H3K9me3 and H3K36me3) and transcriptome sequencing (RNA-seq) in a cohort of primary CLL and healthy B lymphocytes samples (CLL IGHV unmutated, n = 12; CLL IGHV mutated, n = 10; peripheral blood NBCs [CD23+CD19+CD27-IgD+], peripheral blood memory B cells [GCBs; CD23+CD19+CD27+IgD-], peripheral blood CD20+ cells.
Publication Title
Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL.
Sample Metadata Fields
No sample metadata fields
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