Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells.
Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells.
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DOI：
10.1158/0008-5472.can-20-3837
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发表时间：
2021-10-01
期刊：
影响因子：
11.2
通讯作者：
Brunet E
中科院分区：
文献类型：
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作者：
Sole A;Grossetête S;Heintzé M;Babin L;Zaïdi S;Revy P;Renouf B;De Cian A;Giovannangeli C;Pierre-Eugène C;Janoueix-Lerosey I;Couronné L;Kaltenbach S;Tomishima M;Jasin M;Grünewald TGP;Delattre O;Surdez D;Brunet E
尤文肉瘤（EwS）的特征是特异性易位，最常见的融合EWSR 1与FLI 1。估计30%的EwS肿瘤还显示STAG 2、TP 53或CDKN 2A（SPC）的遗传改变。从原代人类细胞开发相关EwS模型的许多尝试在忠实地再现EwS的表型、转录组和表观遗传特征方面都不成功。在这项研究中，通过工程改造t（11;22）（q24;q12）易位与SPC突变的组合，我们产生了广泛的永生化细胞（EWIma细胞）的集合，耐受EWSR 1-FLI 1表达的原代间充质干细胞（MSC）来自EwS患者。在该模型中，SPC改变强烈支持EwS致癌性。用独立的EWIma细胞进行的异种移植实验在小鼠中诱导肿瘤和转移，其显示了EwS的真实特征。EWIma细胞呈现出平衡的，但也更复杂的易位谱，模拟在EwS和其他癌症中经常观察到的染色体易位。总的来说，这些结果表明，骨髓来源的间充质干细胞是来源的EwS，也提供了原始的实验模型，调查尤文肉瘤。这些发现表明尤文肉瘤可以起源于人骨髓间充质干细胞，并且复发性突变支持EWSR 1-FLI 1易位介导的转化。
Ewing sarcoma (EwS) is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of EwS tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). Numerous attempts to develop relevant EwS models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic and epigenetic features of EwS. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from an EwS patient. Within this model, SPC alterations strongly favored EwS oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide features of EwS. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in EwS and other cancers. Collectively, these results demonstrate that bone marrow-derived MSCs are a source of origin for EwS and also provide original experimental models to investigate Ewing sarcomagenesis. These findings demonstrate that Ewing sarcoma can originate from human bone marrow-derived mesenchymal stem cells and that recurrent mutations support EWSR1-FLI1 translocation-mediated transformation.