Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA271644 | ENA |
REPOSITORIES: ENA
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Project description:Oncogenic transformation in Ewing sarcoma tumors is driven by the fusion oncogene EWS-FLI1. The inducible expression of EWS-FLI1 (EF) in embryoid bodies, or collections of differentiating stem cells, generates cells with properties of Ewing sarcoma tumors, including characteristics of transformation. These cell lines exhibit anchorage-independent growth, a lack of contact inhibition and a strong Ewing sarcoma gene expression signature. These cells also demonstrate a requirement for the persistent expression of EWS-FLI1 for cell survival and growth. We used microarrays to detail the effects of doxycycline-inducible expression of EWS-FLI1 on the gene expression signature of cells derived from differentiating stem cells, or embryoid bodies. Triplicate biological replicates were collected and analyzed.
2015-12-31 | E-GEOD-64686 | biostudies-arrayexpress
Project description:Oncogenic transformation in Ewing sarcoma tumors is driven by the fusion oncogene EWS-FLI1. The inducible expression of EWS-FLI1 (EF) in embryoid bodies, or collections of differentiating stem cells, generates cells with properties of Ewing sarcoma tumors, including characteristics of transformation. These cell lines exhibit anchorage-independent growth, a lack of contact inhibition and a strong Ewing sarcoma gene expression signature. These cells also demonstrate a requirement for the persistent expression of EWS-FLI1 for cell survival and growth.
2015-12-31 | GSE64686 | 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. 3 replicate samples for 4 different stem cell populations were analyzed by HuEx arrays. The 4 sample types were adult human bone marrow-derived mesenchymal stem cells, human embryonic stem cell-derived nueral crest stem cells (hNCSC), control vector-transduced hNCSC-derived mesenchymal stem cells (NC-MSC), and EWS-FLI1-transduced hNCSC-derived mesenchymal stem cells (NC-MSC EF). Control and EWS-FLI1 transduced NC-MSC were isolated 5 days after lentiviral transduction. Transcript level expression data was compared among the different populations to determine differences and similarities between NCSC, BM-MSC and NC-MSC with/without EWS-FLI1 expression. These data were used to identify EWS-FLI1 targets in NC-MSC and to characterize the genetic changes that occur in NCSC as they generate NC-MSC progeny.
2010-06-23 | E-GEOD-21511 | biostudies-arrayexpress
Project description:We sequenced embryoid bodies at various time points following induction of pre-mesendoderm cells (PreME) towards primordial germ cell-like cell (PGCLC) fate
2023-05-05 | E-MTAB-11283 | biostudies-arrayexpress
Project description:The mechanisms underlying tumor cell plasticity driving drug resistance and disease progression remain poorly understood. In Ewing sarcoma (EwS), variations in EWS::FLI1 (EF) activity have been associated with epithelial-mesenchymal plasticity (EMP). Using degron technology, we titrated endogenous EF in an EwS cell line and linked phenotypic states to distinct EF thresholds. Strikingly, modest EF depletion promoted a pro-metastatic phenotype, which was diminished upon near-complete EF loss. Transcriptomic analysis revealed distinct gene clusters with heterogenous response patterns to varying EF dosage. Target genes most sensitive to subtle EF depletion contained GGAA microsatellites in EF-bound enhancers. Furthermore, we identified Krüppel-like zinc-finger transcription factors to be associated with EF-repressed EMP genes. EF rescue after partial depletion for a transient period identified persistently dysregulated genes associated with poor prognosis. This study underscores the therapeutic challenge of insufficient EF inhibition and provides a foundation for exploiting oncoprotein dynamics to uncover therapeutic vulnerabilities in fusion-driven cancers.
2025-04-10 | GSE291060 | GEO
Project description:The mechanisms underlying tumor cell plasticity driving drug resistance and disease progression remain poorly understood. In Ewing sarcoma (EwS), variations in EWS::FLI1 (EF) activity have been associated with epithelial-mesenchymal plasticity (EMP). Using degron technology, we titrated endogenous EF in an EwS cell line and linked phenotypic states to distinct EF thresholds. Strikingly, modest EF depletion promoted a pro-metastatic phenotype, which was diminished upon near-complete EF loss. Transcriptomic analysis revealed distinct gene clusters with heterogenous response patterns to varying EF dosage. Target genes most sensitive to subtle EF depletion contained GGAA microsatellites in EF-bound enhancers. Furthermore, we identified Krüppel-like zinc-finger transcription factors to be associated with EF-repressed EMP genes. EF rescue after partial depletion for a transient period identified persistently dysregulated genes associated with poor prognosis. This study underscores the therapeutic challenge of insufficient EF inhibition and provides a foundation for exploiting oncoprotein dynamics to uncover therapeutic vulnerabilities in fusion-driven cancers.
2025-04-10 | GSE291134 | GEO
Project description:The mechanisms underlying tumor cell plasticity driving drug resistance and disease progression remain poorly understood. In Ewing sarcoma (EwS), variations in EWS::FLI1 (EF) activity have been associated with epithelial-mesenchymal plasticity (EMP). Using degron technology, we titrated endogenous EF in an EwS cell line and linked phenotypic states to distinct EF thresholds. Strikingly, modest EF depletion promoted a pro-metastatic phenotype, which was diminished upon near-complete EF loss. Transcriptomic analysis revealed distinct gene clusters with heterogenous response patterns to varying EF dosage. Target genes most sensitive to subtle EF depletion contained GGAA microsatellites in EF-bound enhancers. Furthermore, we identified Krüppel-like zinc-finger transcription factors to be associated with EF-repressed EMP genes. EF rescue after partial depletion for a transient period identified persistently dysregulated genes associated with poor prognosis. This study underscores the therapeutic challenge of insufficient EF inhibition and provides a foundation for exploiting oncoprotein dynamics to uncover therapeutic vulnerabilities in fusion-driven cancers.
2025-04-10 | GSE291133 | GEO
Project description:EWS-FLI1, a multi-functional fusion oncogene, is exclusively detectable in Ewing sarcomas. However, previous studies reported that a subset of osteosarcomas also harbor EWS-ETS family fusion, suggesting that the fusion gene may be involved in the development of a particular type of osteosarcomas. Here using the doxycycline inducible EWS-FLI1 system, we established an EWS-FLI1-dependent osteosarcoma model from murine bone marrow stromal cells. We revealed that the withdrawal of EWS-FLI1 expression enhances the osteogenic differentiation of sarcoma cells, leading to mature bone formation. Taking advantage of induced pluripotent stem cell (iPSC) technology, we also showed that the sarcoma-derived iPSCs with cancer-related genetic abnormalities exhibited the impaired differentiation program of osteogenic lineage irrespective of the EWS-FLI1 expression. Finally, we demonstrated that EWS-FLI1 contributed to in vitro sarcoma development from the sarcoma-iPSCs after osteogenic differentiation. These findings demonstrated that modulating cellular differentiation is fundamental principle of the EWS-FLI1-induced osteosarcoma development. Furthermore, the in vitro cancer model using sarcoma-iPSCs should provide a novel platform for dissecting relationship between cancer genome and cellular differentiation. Microarray in mouse EWS-FLI1-induced osteosarcoma cell lines(SCOS#2 and SCOS#12) and sarcoma(SCOS#2)-derived iPSCs. Total 6 samples were analyzed. We can induce EWS-FLI1 expression by Doxycycline-inducible expression system in SCOS#2 and #12. We investigaed EWS-FLI1 activated genes (Dox ON-High) and EWS-FLI1 repressed genes (Dox OFF-High) in SCOS#2 and #12 sarcoma cell lines. Also, we investigated global gene expression pattern of sarcoma-derived iPSCs (iPSC#2-A1 and #2-B5). A link to this sample file can be found below.
2016-03-01 | E-GEOD-72704 | biostudies-arrayexpress
Project description:EWS-FLI1, a multi-functional fusion oncogene, is exclusively detectable in Ewing sarcomas. However, previous studies reported that a subset of osteosarcomas also harbor EWS-ETS family fusion, suggesting that the fusion gene may be involved in the development of a particular type of osteosarcomas. Here using the doxycycline inducible EWS-FLI1 system, we established an EWS-FLI1-dependent osteosarcoma model from murine bone marrow stromal cells. We revealed that the withdrawal of EWS-FLI1 expression enhances the osteogenic differentiation of sarcoma cells, leading to mature bone formation. Taking advantage of induced pluripotent stem cell (iPSC) technology, we also showed that the sarcoma-derived iPSCs with cancer-related genetic abnormalities exhibited the impaired differentiation program of osteogenic lineage irrespective of the EWS-FLI1 expression. Finally, we demonstrated that EWS-FLI1 contributed to in vitro sarcoma development from the sarcoma-iPSCs after osteogenic differentiation. These findings demonstrated that modulating cellular differentiation is fundamental principle of the EWS-FLI1-induced osteosarcoma development. Furthermore, the in vitro cancer model using sarcoma-iPSCs should provide a novel platform for dissecting relationship between cancer genome and cellular differentiation. Chip-seq in mouse EWS-FLI1-induced osteosarcoma cell lines (SCOS#2 )
2016-03-01 | E-GEOD-72897 | biostudies-arrayexpress
Project description:Transient transfection of a Ewing's Sarcoma cell line expressing type I EWS-FLI1 fusion and doxycycline-inducible short hairpin RNA against EWS-FLI1 (A673sh)
2013-07-01 | GSE37409 | GEO