Human Exon Array Profiling of Ewing sarcoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE16016 | GEO | 2010/06/01
SECONDARY ACCESSION(S): PRJNA115443
REPOSITORIES: GEO
Similar Datasets
Project description:Ewing sarcoma family tumors (ESFTs) are aggressive tumors of putative stem cell origin for which prognostic biomarkers and novel treatments are needed. We have previously shown that the polycomb gene BMI-1 functions as an oncogene in ESFT. In several human cancers, high expression of BMI-1 is associated with poor outcome. For the current study, we evaluated the significance of variable BMI-1 expression levels in a large cohort of primary ESFT. Immunohistochemical staining of 130 tumors revealed that BMI-1 is over-expressed by the vast majority of ESFT. However, in 20% of cases, BMI-1 levels are low to undetectable. Significantly, although clinical presentation and outcome were found to be similar between BMI-1-high and BMI-1-low tumors, gene expression profiling studies showed marked differences in their respective gene expression profiles. Gene specific enrichment analysis identified that several cancer-associated canonical biologic pathways, including IGF1, mTOR and WNT, are significantly down-regulated in BMI-1-low compared to BMI-1-high tumors. Consistent with these in vivo data, in vitro studies of IGF1-R inhibition showed that the growth inhibitory effects of IGF1-R blockade are diminished in BMI-1-low ESFT cells. ESFT that do not over-express BMI-1 represent a novel subclass with a distinct molecular profile and altered activation of cancer-associated pathways. Affy HuEx 1.0 array profiling of 10 primary ESFT samples obtained from patients with newly diagnosed ESFT. 5 confirmed BMI-1 low and 5 confirmed BMI-1 high expressers by immunostaining.
2010-06-08 | E-GEOD-16016 | biostudies-arrayexpress
Project description:Over-expression of the polycomb group gene BMI-1 is implicated in the pathogenesis of many human cancers. In this study, we investigate the role of BMI-1 as a functional oncogene in the Ewing’s Sarcoma Family of Tumors (ESFT), a highly aggressive group of bone and soft tissue tumors. Our data show that BMI-1 is highly expressed by the majority of primary ESFT and ESFT cell lines. However, in contrast to previous reports in other human cancer cell types, knockdown of BMI-1 in ESFT cell lines has no effect on cell survival. Instead, gain and loss of function studies in vitro and in vivo demonstrate that BMI-1 promotes the anchorage independent growth and tumorigenicity of ESFT. Importantly, we also find that modulation of BMI-1 alters the tumorigenicity of both p16-wild type and p16-null cell lines and that BMI-1-mediated effects on growth promotion are independent of CDKN2a repression. Gene expression profiling of ESFT cells following BMI-1 modulation reveals novel downstream effectors of BMI-1 function including key developmental, cell:cell and cell:matrix adhesion pathways. These data support a central role for BMI-1 in the pathogenesis of ESFT and reveal that p16-independent functions of BMI-1 are largely responsible for its oncogenic function in this tumor family. Keywords: Modification of BMI-1 expression in ESFT cell lines
2008-07-18 | GSE12064 | GEO
Project description:Obesity is thought to contribute to worse disease outcome in breast cancer as a result of increased levels of adipocyte-secreted endocrine factors, insulin, and insulin-like growth factors (IGFs) that accelerate tumor cell proliferation and impair treatment response. We examined the effects of patient obesity on primary breast tumor gene expression, by profiling transcription of a set of tumors for which the patients’ body mass index (BMI) was ascertained. Sample profiles were stratified according to patients’ obesity phenotype defined as normal (BMI <25), overweight (BMI 25-29.9), or obese (BMI>30). Widespread alterations in gene expression were evident in breast tumors from obese patients as compared to tumors from other patients, allowing us to define an obesity-associated cancer transcriptional signature of 662 genes. Keywords: two group comparison Primary breast tumor specimens were obtained from patients. Study volunteers completed questionnaires used to define historically normal (BMI<=24.9), overweight (BMI 25-29.9), or obese (BMI>=30) patient categories according to established WHO criteria.
2011-07-17 | E-GEOD-24185 | biostudies-arrayexpress
Project description:Obesity is thought to contribute to worse disease outcome in breast cancer as a result of increased levels of adipocyte-secreted endocrine factors, insulin, and insulin-like growth factors (IGFs) that accelerate tumor cell proliferation and impair treatment response. We examined the effects of patient obesity on primary breast tumor gene expression, by profiling transcription of a set of tumors for which the patients’ body mass index (BMI) was ascertained. Sample profiles were stratified according to patients’ obesity phenotype defined as normal (BMI <25), overweight (BMI 25-29.9), or obese (BMI>30). Widespread alterations in gene expression were evident in breast tumors from obese patients as compared to tumors from other patients, allowing us to define an obesity-associated cancer transcriptional signature of 662 genes. Keywords: two group comparison
2011-07-18 | GSE24185 | GEO
Project description:Hypoxia is an important condition in the tumor cell microenvironment and approximately 1-1.5% of the genome is transcriptionally responsive to hypoxia with hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. By immunohistochemical analysis, HIF-1α expression was readily detectable in 18/28 primary Ewing´s sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, which encouraged us to study the effect of hypoxia on ESFT cell lines in vitro. Many tumors are profoundly hypoxic and multiple studies have demonstrated that hypoxic tumors have a poorer prognosis than non-hypoxic tumors. The cellular adaptations of cancer cells to hypoxia have been shown to profoundly influence transcriptional regulation. Intriguingly, we found that EWS-FLI1 protein expression, which characterizes ESFT, is up-regulated by hypoxia in a HIF-1α-dependent manner. Hypoxia modulated the EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of EWS-FLI1 and of hypoxia were observed. Consistent with alterations in the expression of metastasis related genes, hypoxia stimulated the invasiveness and soft-agar colony formation of ESFT cells in vitro. Our data represents the first transcriptome analysis of hypoxic ESFT cells and identifies hypoxia as an important microenvironmental factor modulating EWS-FLI1 expression and target gene activity with far-reaching consequences for the malignant properties of ESFT. Experiment Overall Design: We analysed the consequences of hypoxia on gene expression in two ESFT cell lines (SK-N-MC, TC252) grown as multicellular spheroids and as adherent monolayers.
2010-02-05 | E-GEOD-19197 | biostudies-arrayexpress
Project description:Hypoxia is an important condition in the tumor cell microenvironment and approximately 1-1.5% of the genome is transcriptionally responsive to hypoxia with hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. By immunohistochemical analysis, HIF-1α expression was readily detectable in 18/28 primary Ewing´s sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, which encouraged us to study the effect of hypoxia on ESFT cell lines in vitro. Many tumors are profoundly hypoxic and multiple studies have demonstrated that hypoxic tumors have a poorer prognosis than non-hypoxic tumors. The cellular adaptations of cancer cells to hypoxia have been shown to profoundly influence transcriptional regulation. Intriguingly, we found that EWS-FLI1 protein expression, which characterizes ESFT, is up-regulated by hypoxia in a HIF-1α-dependent manner. Hypoxia modulated the EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of EWS-FLI1 and of hypoxia were observed. Consistent with alterations in the expression of metastasis related genes, hypoxia stimulated the invasiveness and soft-agar colony formation of ESFT cells in vitro. Our data represents the first transcriptome analysis of hypoxic ESFT cells and identifies hypoxia as an important microenvironmental factor modulating EWS-FLI1 expression and target gene activity with far-reaching consequences for the malignant properties of ESFT. Keywords: Consequences on gene expression of hypoxic condition created by exposure of cells to 1% oxygen in a hypoxia chamber.
2010-05-26 | GSE19197 | GEO
Project description:Ewing sarcoma family of tumors (ESFT) are aggressive bone and soft tissue tumors of unknown cellular origin. Most ESFT express EWS-FLI1, a chimeric protein which functions as a growth-promoting oncogene in ESFT but is toxic to most normal cells. A major difficulty in understanding EWS-FLI1 function has been the lack of an adequate model in which to study EWS-FLI1-induced transformation. Although the cell of origin of ESFT remains elusive, both mesenchymal (MSC) and neural crest (NCSC) have been implicated. We recently developed the tools to generate NCSC from human embryonic stem cells (hNCSC). In the current study we used this model to test the hypothesis that neural crest-derived stem cells are the cells of origin of ESFT and to evaluate the consequences of EWS-FLI1 expression on human neural crest biology. hNCSC transduced with an EWS-FLI1 lentivirus tolerated expression of the oncoprotein. Moreover, EWS-FLI1-transduced hNCSC continued to proliferate and maintain EWS-FLI1 expression in culture for several weeks after transduction. Affymetrix HuEx 1.0 expression profiling of hNCSC cells five days post-transduction with EWS-FLI1 demonstrated the expected induction and repression of well-established EWS-FLI1 targets and also identified numerous other novel EWS-FLI1-regulated genes that are likely to be cell-type and situation specific. In particular, the EWS-FLI1 repressive signature was found to be highly context dependent. Moreover, while control vector transduced cells displayed an MSC-like phenotype, EWS-FLI1-transduced cells maintained a NCSC-like phenotype and genetic profiling revealed reprogramming towards a more pluriopotent, neuroectodermal state. Finally, EWS-FLI1 expressing cells upregulated expression of the polycomb proteins BMI-1 and EZH2. These data implicate neural crest-derived cells in the origin of ESFT and suggest that EWS-FLI1 enables malignant transformation by inducing maintenance of a multipotent, NCSC-state through deregulation of polycomb genes.
2010-06-15 | GSE21511 | GEO
Project description:EWS-FLI1 is a chimeric ETS transcription factor that is, due to a chromosomal rearrangement, specifically expressed in Ewing’s sarcoma family tumors (ESFT) and is thought to be the initiating event in the development of the disease. Previous genomic profiling experiments have identified a number of EWS-FLI1 regulated genes and genes that discriminate ESFT from other sarcomas, but so far a comprehensive analysis of EWS-FLI1 dependent molecular functions characterizing this aggressive cancer is lacking. In this study a molecular function map of ESFT was constructed based on an integrative analysis of gene expression profiling experiments on a uniform microarray platform following EWS-FLI1 knockdown in a panel of five ESFT cell lines, and on gene expression data from the same platform of 59 primary ESFT tumors. Based on the assumption that EWS-FLI1 is the driving transcriptional force in ESFT pathogenesis, we predicted an inverse correlation of gene expression for EWS-FLI1 regulated genes between the putative tissue of origin and the cell lines under EWS-FLI1 knockdown conditions. Consistent with recent reports, mesenchymal progenitor cells (MPC) were found to fit this hypothesis best and were therefore used as the reference tissue for the construction of the molecular function map in ESFT. The interrelations of molecular pathways were visualized by measuring the similarity among annotated gene functions by gene sharing. The molecular function map highlighted distinct clusters of activities for EWS-FLI1 regulated genes in ESFT and revealed a striking difference between EWS-FLI1 up- and down-regulated genes: EWS-FLI1 induced genes mainly belong to cell cycle regulation, proliferation and response to DNA damage, while repressed genes were associated with differentiation and cell communication. This study revealed that EWS-FLI1 combines by distinct molecular mechanisms two important functions of cellular transformation in one protein, growth promotion and differentiation blockage. By taking MPC as a reference tissue a significant EWS-FLI1 signature was discovered in ESFT that only partially overlapped with previously published EWS-FLI1 dependent gene expression patterns, identifying a series of novel targets for the chimeric protein in ESFT. Our results may guide target selection for future ESFT specific therapies. Keywords: Ewing's Sarcoma, EWS-FLI1, RNAi knock down and controls
2009-04-30 | GSE14543 | GEO
Project description:Ewing’s sarcoma family of tumors (ESFT) is an aggressive pediatric bone and soft tissue cancer. It is the prototypical example of mesenchymal tumors driven by a fusion oncogene involving the ewing sarcoma break point region 1 (EWSR1) gene, most frequently– EWS-FLI1. We have discovered that loss of EWSR1 leads to accumulation of R-loops, replication stress and impaired homologous recombination, recapitulating breast cancer 1, early onset (BRCA1) deficiency. EWS-FLI1 acts dominant negatively in ESFT to impart the same phenotypes. Further we demonstrate that in ESFT, BRCA1 predominantly associates with the elongating transcription machinery and is unavailable for DNA strand break repair. Gene expression profiling identified upregulated compensatory mechanisms in ESFT cells to process increased R-loops (RNASEH2 and FEN1) and replication stress (Fanconi Anemia). Taken together, our data identifies BRCA1 sequestration due to transcription stress as the mechanistic basis for ESFT chemosensitivity and suggests potential targets for the much lacking second-line therapy.
2018-03-09 | GSE68845 | GEO
Project description:Ewing’s sarcoma family of tumors (ESFT) is an aggressive pediatric bone and soft tissue cancer. It is the prototypical example of mesenchymal tumors driven by a fusion oncogene involving the ewing sarcoma break point region 1 (EWSR1) gene, most frequently– EWS-FLI1. We have discovered that loss of EWSR1 leads to accumulation of R-loops, replication stress and impaired homologous recombination, recapitulating breast cancer 1, early onset (BRCA1) deficiency. EWS-FLI1 acts dominant negatively in ESFT to impart the same phenotypes. Further we demonstrate that in ESFT, BRCA1 predominantly associates with the elongating transcription machinery and is unavailable for DNA strand break repair. Gene expression profiling identified upregulated compensatory mechanisms in ESFT cells to process increased R-loops (RNASEH2 and FEN1) and replication stress (Fanconi Anemia). Taken together, our data identifies BRCA1 sequestration due to transcription stress as the mechanistic basis for ESFT chemosensitivity and suggests potential targets for the much lacking second-line therapy.
2018-03-09 | GSE68836 | GEO