title: Modeling the initiation of Ewing sarcoma tumorigenesis in differentiating human embryonic stem cells.
abstract: Oncogenic transformation in Ewing sarcoma tumors is driven by the fusion oncogene EWS-FLI1. However, despite the well-established role of EWS-FLI1 in tumor initiation, the development of models of Ewing sarcoma in human cells with defined genetic elements has been challenging. Here, we report a novel approach to model the initiation of Ewing sarcoma tumorigenesis that exploits the developmental and pluripotent potential of human embryonic stem cells. The inducible expression of EWS-FLI1 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. Furthermore, these cells also demonstrate a requirement for the persistent expression of EWS-FLI1 for cell survival and growth, which is a hallmark of Ewing sarcoma tumors.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Gordon
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Motwani
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Cell Biology, Harvard Medical School, Boston, MA, USA.|Howard Hughes Medical Institute, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Pellman
mesh_terms: D063646:Carcinogenesis; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D058732:Embryoid Bodies / Q000473:pathology / Q000502:physiology; D053595:Embryonic Stem Cells / Q000473:pathology* / Q000502:physiology*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics; D034802:RNA-Binding Protein EWS / Q000235:genetics; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000473:pathology*
chemical_list: C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS