Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells

G-A Franzetti; K Laud-Duval; W van der Ent; A Brisac; M Irondelle; S Aubert; U Dirksen; C Bouvier; G de Pinieux; E Snaar-Jagalska; P Chavrier; O Delattre

doi:10.1038/onc.2016.498

Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells

Oncogene. 2017 Jun 22;36(25):3505-3514. doi: 10.1038/onc.2016.498. Epub 2017 Jan 30.

Authors

G-A Franzetti^{1

2}, K Laud-Duval^{1

2}, W van der Ent^{1

2

3}, A Brisac^{1

2}, M Irondelle^{1

4

5}, S Aubert⁶, U Dirksen⁷, C Bouvier⁸, G de Pinieux⁹, E Snaar-Jagalska³, P Chavrier^{1

4}, O Delattre^{1

2}

Affiliations

¹ Institut Curie, PSL Research University, Paris cedex 05, France.
² INSERM U830, Genetic and Biology of Pediatric Tumors group, Institut Curie Research Center, Paris, France.
³ Institute of Biology, Leiden University, Leiden, The Netherlands.
⁴ UMR144, Membrane and Cytoskeleton Dynamics group, Institut Curie Research Center, Paris, France.
⁵ UMR144, Cell and Tissue Imaging Facility (PICT IBiSA), Institut Curie Research Center, Paris, France.
⁶ Department of Pathology, University Hospital, Lille, France.
⁷ Department of Pediatric Hematology and Oncology, University Hospital Muenster, Albert-Schweitzer Campus 1, A1 and Westfalian Wilhelms University, Muenster, Germany.
⁸ Department of Pathology, La Timone University Hospital, Marseille, France.
⁹ Department of Pathology, University Hospital of Tours and University François Rabelais, Chambray-lès-Tours, France.

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-FLI1^high states, characterized by highly active cell proliferation, and EWSR1-FLI1^low states 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calmodulin-Binding Proteins / biosynthesis*
Calmodulin-Binding Proteins / genetics
Cell Line, Tumor
Cell Movement*
Cell Proliferation*
Gene Expression Regulation, Neoplastic*
Mice
Mice, SCID
Neoplasm Invasiveness
Neoplasm Metastasis
Oncogene Proteins, Fusion / biosynthesis*
Oncogene Proteins, Fusion / genetics
Proto-Oncogene Protein c-fli-1 / biosynthesis*
Proto-Oncogene Protein c-fli-1 / genetics
RNA-Binding Protein EWS
RNA-Binding Proteins / biosynthesis*
RNA-Binding Proteins / genetics
Sarcoma, Ewing / genetics
Sarcoma, Ewing / metabolism*
Sarcoma, Ewing / pathology
Zebrafish

Substances

Calmodulin-Binding Proteins
Ewsr1 protein, mouse
Fli1 protein, mouse
Oncogene Proteins, Fusion
Proto-Oncogene Protein c-fli-1
RNA-Binding Protein EWS
RNA-Binding Proteins