CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma.
CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma.
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DOI：
10.1158/0008-5472.can-16-3351
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发表时间：
2017-06-01
期刊：
影响因子：
11.2
通讯作者：
Nakamura T
中科院分区：
文献类型：
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作者：
Yoshimoto T;Tanaka M;Homme M;Yamazaki Y;Takazawa Y;Antonescu CR;Nakamura T
CIC-DUX4肉瘤（CDS）或cic -重排肉瘤是小圆细胞肉瘤的一个亚类，类似于Ewing肉瘤（ES）的形态表型。然而，最近的临床病理和分子遗传学分析表明，CDS是一个独立于ES的疾病实体。很少有辅助标记物用于CDS的鉴别诊断，并且需要额外的CDS特异性生物标记物进行更明确的分类。在这里，我们报告了用人CIC-DUX4 cDNA转导胚胎间充质细胞（eMC）产生离体小鼠CDS模型。受体小鼠移植表达CIC-DUX4的eMC后，迅速形成由小圆到短梭形细胞组成的侵袭性未分化肉瘤。CDS和eMC的基因表达谱显示CIC-DUX4下游基因PEA3家族基因、Ccnd2、Crh和Zic1表达上调。小鼠和人类肿瘤的免疫组织化学分析表明，CCND2和MUC5AC是区分CDS和ES的可靠生物标志物。基因沉默CIC-DUX4、Ccnd2、Ret、Bcl2能有效抑制体外培养的CDS肿瘤生长。CDK4/6抑制剂palbociclib和软组织肉瘤药物trabectedin也能阻断小鼠CDS的生长。总之，我们的小鼠模型提供了关于CDS的重要生物学信息，并为探索CDS的生物标志物和治疗剂提供了一个有用的平台。
CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). Hoever, recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Few ancillary markers have been used in the differential diagnosis of CDS, and additional CDS-specific biomarkers are needed for more definitive classification. Here we report the generation of an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMC) with human CIC-DUX4 cDNA. Recipient mice transplanted with eMC expressing CIC-DUX4 rapidly developed an aggressive, undifferentiated sarcoma composed of small-round to short-spindle cells. Gene expression profiles of CDS and eMC revealed upregulation of CIC-DUX4 downstream genes such as PEA3 family genes, Ccnd2, Crh and Zic1. Immunohistochemical analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2 effectively inhibited CDS tumor growth in vitro. The CDK4/6 inhibitor palbociclib and the soft tissue sarcoma drug trabectedin also blocked the growth of mouse CDS. In summary, our mouse model provides important biological information about CDS and provides a useful platform to explore biomarkers and therapeutic agents for CDS.