title: Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells.
abstract: Ewing sarcoma is characterized by the expression of the chimeric EWSR1-FLI1 transcription factor. Proteomic analyses indicate that the decrease of EWSR1-FLI1 expression leads to major changes in effectors of the dynamics of the actin cytoskeleton and the adhesion processes with a shift from cell-to-cell to cell-matrix adhesion. These changes are associated with a dramatic increase of in vivo cell migration and invasion potential. Importantly, EWSR1-FLI1 expression, evaluated by single-cell RT-ddPCR/immunofluorescence analyses, and activity, assessed by expression of EWSR1-FLI1 downstream targets, are heterogeneous in cell lines and in tumours and can fluctuate along time in a fully reversible process between EWSR1-FLI1highstates, characterized by highly active cell proliferation, and EWSR1-FLI1lowstates where cells have a strong propensity to migrate, invade and metastasize. This new model of phenotypic plasticity proposes that the dynamic fluctuation of the expression level of a dominant oncogene is an intrinsic characteristic of its oncogenic potential.
authors.affiliation: Institut Curie, PSL Research University, Paris cedex 05, France.|INSERM U830, Genetic and Biology of Pediatric Tumors group, Institut Curie Research Center, Paris, France.
authors.forename: G-A
authors.initials: GA
authors.lastname: Franzetti
authors.affiliation: Institut Curie, PSL Research University, Paris cedex 05, France.|INSERM U830, Genetic and Biology of Pediatric Tumors group, Institut Curie Research Center, Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Laud-Duval
authors.affiliation: Institut Curie, PSL Research University, Paris cedex 05, France.|INSERM U830, Genetic and Biology of Pediatric Tumors group, Institut Curie Research Center, Paris, France.|Institute of Biology, Leiden University, Leiden, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: van der Ent
authors.affiliation: Institut Curie, PSL Research University, Paris cedex 05, France.|INSERM U830, Genetic and Biology of Pediatric Tumors group, Institut Curie Research Center, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Brisac
authors.affiliation: Institut Curie, PSL Research University, Paris cedex 05, France.|UMR144, Membrane and Cytoskeleton Dynamics group, Institut Curie Research Center, Paris, France.|UMR144, Cell and Tissue Imaging Facility (PICT IBiSA), Institut Curie Research Center, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Irondelle
authors.affiliation: Department of Pathology, University Hospital, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Aubert
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital Muenster, Albert-Schweitzer Campus 1, A1 and Westfalian Wilhelms University, Muenster, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Dirksen
authors.affiliation: Department of Pathology, La Timone University Hospital, Marseille, France.
authors.forename: C
authors.initials: C
authors.lastname: Bouvier
authors.affiliation: Department of Pathology, University Hospital of Tours and University François Rabelais, Chambray-lès-Tours, France.
authors.forename: G
authors.initials: G
authors.lastname: de Pinieux
authors.affiliation: Institute of Biology, Leiden University, Leiden, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Snaar-Jagalska
authors.affiliation: Institut Curie, PSL Research University, Paris cedex 05, France.|UMR144, Membrane and Cytoskeleton Dynamics group, Institut Curie Research Center, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Chavrier
authors.affiliation: Institut Curie, PSL Research University, Paris cedex 05, France.|INSERM U830, Genetic and Biology of Pediatric Tumors group, Institut Curie Research Center, Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Delattre
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000096:biosynthesis* / Q000235:genetics; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015027:Zebrafish
chemical_list: D002148:Calmodulin-Binding Proteins; C000605150:Ewsr1 protein, mouse; C497426:Fli1 protein, mouse; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins