Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma
Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma
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DOI：
10.1158/0008-5472.can-08-3723
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发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
Keller, Charles
中科院分区：
文献类型：
--
作者：
Nishijo, Koichi;Chen, Qing-Rong;Keller, Charles
高度侵袭性的肌肉癌腺泡状横纹肌肉瘤（ARMS）是儿童最常见的软组织肉瘤之一，然而，不可切除和转移性疾病的结果是令人沮丧的，并且近三十年来没有变化。为了更好地理解这种疾病的发病机制并促进新的临床前方法，我们先前通过忠实地重现在人类疾病中观察到的基因突变，即，Pax3.Fkhr融合基因的激活与p53或Cdkn 2a失活。在这份报告中，我们表明，该模型概括了免疫组化概况和人类疾病的快速进展。我们发现Pax3.Fkhr表达在晚期癌前病变中增加，但发生转移的肿瘤细胞明显受到Pax3.Fkhr表达的选择。在全基因组水平上，跨物种基因集富集分析和元基因投射研究表明，与其他儿科癌症相比，我们的小鼠模型与人类ARMS最相似。我们已经定义了小鼠和人ARMS之间保守的表达谱，以及Pax3.Fkhr签名，包括靶基因SKP 2。我们进一步鉴定了7种跨物种过表达的“可药用”激酶。这些数据证实了这种基因工程小鼠模型的准确性。[Cancer Res 2009;69（7）：2902-11]
The highly aggressive muscle cancer alveolar rhabdomyosarcoma (ARMS) is one of the most common soft tissue sarcoma of childhood, yet the outcome for the unresectable and metastatic disease is dismal and unchanged for nearly three decades. To better understand the pathogenesis of this disease and to facilitate novel preclinical approaches, we previously developed a conditional mouse model of ARMS by faithfully recapitulating the genetic mutations observed in the human disease, i.e., activation of Pax3.Fkhr fusion gene with either p53 or Cdkn2a inactivation. In this report, we show that this model recapitulates the immunohistochemical profile and the rapid progression of the human disease. We show that Pax3.Fkhr expression increases during late preneoplasia but tumor cells undergoing metastasis are under apparent selection for Pax3.Fkhr expression. At a whole-genome level, a cross-species gene set enrichment analysis and metagene projection study showed that our mouse model is most similar to human ARMS when compared with other pediatric cancers. We have defined an expression profile conserved between mouse and human ARMS, as well as a Pax3.Fkhr signature, including the target gene, SKP2. We further identified 7 "druggable" kinases overexpressed across species. The data affirm the accuracy of this genetically engineered mouse model. [Cancer Res 2009;69(7):2902-11]