Franzetti G-A, Laud-Duval K, van der Ent W, Brisac A, Irondelle M, Aubert S, Dirksen U, Bouvier C, de Pinieux G, Snaar-Jagalska E, Chavrier P, Delattre O
Institut Curie, PSL Research University, Paris cedex 05, France.
INSERM U830, Genetic and Biology of Pediatric Tumors group, Institut Curie Research Center, Paris, France.
Oncogene. 2017 Jun 22;36(25):3505-3514. doi: 10.1038/onc.2016.498. Epub 2017 Jan 30.
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 states, characterized by highly active cell proliferation, and EWSR1-FLI1 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.
尤因肉瘤的特征是嵌合型EWSR1-FLI1转录因子的表达。蛋白质组学分析表明，EWSR1-FLI1表达的降低会导致肌动蛋白细胞骨架动力学效应器以及黏附过程发生重大变化，从细胞间黏附转变为细胞与基质黏附。这些变化与体内细胞迁移和侵袭潜能的显著增加有关。重要的是，通过单细胞RT-ddPCR/免疫荧光分析评估的EWSR1-FLI1表达以及通过EWSR1-FLI1下游靶点表达评估的活性，在细胞系和肿瘤中是异质的，并且在以高活性细胞增殖为特征的EWSR1-FLI1状态与细胞具有强烈迁移、侵袭和转移倾向的EWSR1-FLI1状态之间的完全可逆过程中，会随时间波动。这种新的表型可塑性模型表明，显性癌基因表达水平的动态波动是其致癌潜能的内在特征。
