PPARγ agonists enhance ET-743-induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma
PPARγ agonists enhance ET-743-induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma
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DOI：
10.1172/jci60015
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发表时间：
2012-03-01
影响因子：
15.9
通讯作者：
Matushansky, Igor
中科院分区：
文献类型：
--
作者：
Charytonowicz, Elizabeth;Terry, Melissa;Matushansky, Igor
粘液样圆细胞脂肪肉瘤（MRCLS）是一种常见的脂肪肉瘤亚型，其特征是易位，导致融合蛋白TLS：CHOP以及混合脂肪细胞组织病理学。MRCLS的病因学和TLS：CHOP的作用机制仍然知之甚少。先前显示，ET-743是一种作用机制尚不清楚的抗肿瘤化合物，对MRCLS患者非常有效。为了鉴定MRCLS的细胞来源，我们设计了一种小鼠模型，其中TLS：CHOP在p53耗尽背景中在中胚层限制性启动子（Prx 1）的控制下表达。该模型在组织学上和功能上类似于MRCLS，其特异性脂肪细胞分化对ET-743的反应。具体地，表达TLS：CHOP的内源性间充质干细胞（MSC）在体内发育成MRCLS。这些MSCs的基因表达和microRNA分析表明，它们致力于脂肪细胞分化，但不能终末分化。我们还探讨了ET-743的作用方式。ET-743下调TLS：CHOP表达，其与CEBP α表达和脂肪细胞分化相关。此外，PPAR γ激动剂增强了ET-743启动的分化过程。我们的工作强调了临床观察如何导致小鼠模型的产生，该模型重现了人类疾病，并可用于开发合理的治疗组合，如ET-743加PPAR γ激动剂，用于治疗MRCLS。
Myxoid round cell liposarcoma (MRCLS) is a common liposarcoma subtype characterized by a translocation that results in the fusion protein TLS:CHOP as well as by mixed adipocytic histopathology. Both the etiology of MRCLS and the mechanism of action of TLS:CHOP remain poorly understood. It was previously shown that ET-743, an antitumor compound with an unclear mechanism of action, is highly effective in patients with MRCLS. To identify the cellular origin of MRCLS, we engineered a mouse model in which TLS:CHOP was expressed under the control of a mesodermally restricted promoter (Prx1) in a p53-depleted background. This model resembled MRCLS histologically as well as functionally in terms of its specific adipocytic differentiation-based response to ET-743. Specifically, endogenous mesenchymal stem cells (MSCs) expressing TLS: CHOP developed into MRCLS in vivo. Gene expression and microRNA analysis of these MSCs showed that they were committed to adipocytic differentiation, but unable to terminally differentiate. We also explored the method of action of ET-743. ET-743 downregulated TLS:CHOP expression, which correlated with CEBP alpha expression and adipocytic differentiation. Furthermore, PPAR gamma agonists enhanced the differentiation process initiated by ET-743. Our work highlights how clinical observations can lead to the generation of a mouse model that recapitulates human disease and may be used to develop rational treatment combinations, such as ET-743 plus PPAR gamma agonists, for the treatment of MRCLS.