Homo sapiens
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PROVIDER: PRJNA152971 | ENA |
REPOSITORIES: ENA
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Project description:Ewing sarcoma, an osteolytic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. In this study, we identified the pro-metastatic gene DKK2 as a highly overexpressed gene in Ewing sarcoma compared with corresponding normal tissues. Using RNA interference, we showed that DKK2 was critical for malignant cell outgrowth in vitro and in an orthotopic xenograft mouse model in vivo. Analysis of invasion potential in both settings revealed a strong correlation of DKK2 expression to Ewing sarcoma invasiveness that may be mediated by the DKK effector matrix metalloproteinase 1 (MMP1). Furthermore, gene expression analyses established the ability of DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2, and TGFb1 that are associated with homing, invasion, and growth of cancer cells in bone tissue as well as genes important for osteolysis, including HIF1a, JAG1, IL6, and VEGF. DKK2 promoted bone infiltration and osteolysis in vivo and further analyses defined DKK2 as a key factor in osteotropic malignancy. Interestingly, in Ewing sarcoma cells, DKK2 suppression simultaneously increased the potential for neuronal differentiation while decreasing chondrogenic and osteogenic differentiation. Our results provide strong evidence that DKK2 is a key player in Ewing sarcoma invasion and osteolysis and also in the differential phenotype of Ewing sarcoma cells.
2012-12-21 | GSE36100 | GEO
Project description:Ewing tumors (ET) are osteolytic bone cancers mostly affecting children and young adults, and are characterized by early lung and distant bone metastases. Here we identified the dickkopf 2 homolog (DKK2) as a highly over-expressed gene in ET compared to normal tissues, which is critically involved in ET aggressiveness. Using RNA interference, we show that DKK2 promotes anchorage-independent colony formation and proliferation of ET cells in vitro and tumorigenicity in vivo. Analysis of the invasion potential in vitro and in an orthotopic bone xenotransplantation model revealed a strong correlation of DKK2 expression and ET invasiveness that is possibly mediated by its downstream effector matrix metallopeptidase 1 (MMP1). Gene expression analyses proved DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2 and TGFβ1, that are associated with homing, invasion and growth of cancer cells in bone tissue. Moreover, we observed that DKK2 promotes bone infiltration and osteolysis in vivo. Interestingly suppression of DKK2 expression increases neuronal differentiation, but at the same time decreases chondrogenic and osteogenic differentiation of ET cells. These data provide evidence that DKK2 is a key player in ET invasiveness and osteotropism, indicating a critical role of DKK2 for malignancy and the differential phenotype of ET. 6 samples (3x A673 cells; 3x SK-N-MC cells); for each cell line one sample was transfected with control non silencing siRNA and one sample with DKK2 siRNA (siDKK2_1) and one sample with ITM2A siRNA (siITM2A_7) as an independent knock down.
2012-12-21 | E-GEOD-36100 | biostudies-arrayexpress
Project description:Induction of epididymis specific G-protein coupled receptor-64 (GPR64) in Ewing Tumors supports invasiveness and metastatic spread
| PRJNA129883 | ENA
Project description:Metastatic spread in Ewing Tumors (ET) is hematogenous and malignant features have been shown to correlate with hypoxia and angiogenesis. We identified several Ewing tumor specific genes (Staege MS et al. Cancer Res. 2004;64:8213-21). Microarray analysis confirmed an endothelial signature of this tumor and revealed the G-protein coupled receptor-64 (GPR64), an orphan receptor with normal expression restricted to human epididymis, to be highly induced in ET. Down-regulation of GPR64 in ET lines by RNA interference did not reduce their proliferative capacity in vitro as measured by plastic adherence dependent proliferation or contact independent growth in colony forming assays. Of interest inhibition of GPR64 expression in ET cell lines resulted in impaired endothelial differentiation in tube formation assays. Furthermore, GPR64 suppression substantially inhibited tumor growth and metastatic spread in immunodeficient Rag2-/-gammaC-/- mice. Microarray analysis of ET after GPR64 knock down revealed a GPR64-mediated induction of VEGF receptor 1 ligand placental growth factor (PGF) in ET. PGF itself was induced by EWS-FLI1 in mesenchymal stem cells. Repression of PGF expression in ET cell lines resulted in a similar phenotype as observed after GPR64 knockdown. GPR64 as well as PGF knock down correlated with a reduced proteolytic activity of Matrix Metalloproteinase MMP1 and invasiveness in vitro. MMP1 specific knock down resulted in the abrogation of metastasis of ET in Rag2-/-gammaC-/- mice. We conclude, that GPR64 and subsequent PGF up-regulation in ET orchestrate and promote endothelial invasiveness and metastatic spread and play a pivotal role in the pathogenesis and aggressiveness of this tumor. Established Ewing tumor cell lines were transfected with siRNA with specificity for CHM1 (control) or GPR64. RNA was extracted and hybridized with Affymetrix HG_U133A microarrays.
2011-09-29 | E-GEOD-23058 | biostudies-arrayexpress
Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.
2018-02-07 | PXD007909 | Pride
Project description:Metastatic spread in Ewing Tumors (ET) is hematogenous and malignant features have been shown to correlate with hypoxia and angiogenesis. We identified several Ewing tumor specific genes (Staege MS et al. Cancer Res. 2004;64:8213-21). Microarray analysis confirmed an endothelial signature of this tumor and revealed the G-protein coupled receptor-64 (GPR64), an orphan receptor with normal expression restricted to human epididymis, to be highly induced in ET. Down-regulation of GPR64 in ET lines by RNA interference did not reduce their proliferative capacity in vitro as measured by plastic adherence dependent proliferation or contact independent growth in colony forming assays. Of interest inhibition of GPR64 expression in ET cell lines resulted in impaired endothelial differentiation in tube formation assays. Furthermore, GPR64 suppression substantially inhibited tumor growth and metastatic spread in immunodeficient Rag2-/-gammaC-/- mice. Microarray analysis of ET after GPR64 knock down revealed a GPR64-mediated induction of VEGF receptor 1 ligand placental growth factor (PGF) in ET. PGF itself was induced by EWS-FLI1 in mesenchymal stem cells. Repression of PGF expression in ET cell lines resulted in a similar phenotype as observed after GPR64 knockdown. GPR64 as well as PGF knock down correlated with a reduced proteolytic activity of Matrix Metalloproteinase MMP1 and invasiveness in vitro. MMP1 specific knock down resulted in the abrogation of metastasis of ET in Rag2-/-gammaC-/- mice. We conclude, that GPR64 and subsequent PGF up-regulation in ET orchestrate and promote endothelial invasiveness and metastatic spread and play a pivotal role in the pathogenesis and aggressiveness of this tumor.
2011-09-30 | GSE23058 | GEO