Effects of RAS on the genesis of embryonal rhabdomyosarcoma
Effects of RAS on the genesis of embryonal rhabdomyosarcoma
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DOI：
10.1101/gad.1545007
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发表时间：
2007-06-01
影响因子：
10.5
通讯作者：
Zon, Leonard I.
中科院分区：
文献类型：
--
作者：
Langenau, David M.;Keefe, Matthew D.;Zon, Leonard I.
胚胎横纹肌肉瘤(ERMS)是一种具有特定肌肉分化特征的癌症，可由RAS家族成员的突变激活引起。然而，到目前为止，RAS通路在大多数ERMS患者中的激活还没有报道。在这里，我们创建了一个斑马鱼RAS诱导的ERM模型，在该模型中，动物在10天的生命中会出现外部可见的肿瘤。微阵列分析和跨物种比较发现，在斑马鱼和人类ERM中都发现了两个保守的基因签名，一个与横纹肌肉瘤中肿瘤特异性和组织限制性基因表达有关，另一个包含新的RAS诱导的基因签名。值得注意的是，我们的分析发现RAS通路激活在人类RMS中非常常见。我们还创造了一种新的转基因共注射方法，根据肌肉分化状态来荧光标记不同的肿瘤细胞亚群。结合荧光激活细胞分选、细胞移植和有限稀释分析，我们能够在斑马鱼ERMS中鉴定出癌症干细胞。当结合对该细胞群体的基因表达研究时，我们认为斑马鱼RMS癌症干细胞与激活的卫星细胞具有相似的自我更新计划。
Embryonal rhabdomyosarcoma (ERMS) is a devastating cancer with specific features of muscle differentiation that can result from mutational activation of RAS family members. However, to date, RAS pathway activation has not been reported in a majority of ERMS patients. Here, we have created a zebrafish model of RAS- induced ERMS, in which animals develop externally visible tumors by 10 d of life. Microarray analysis and cross- species comparisons identified two conserved gene signatures found in both zebrafish and human ERMS, one associated with tumor-specific and tissue-restricted gene expression in rhabdomyosarcoma and a second comprising a novel RAS-induced gene signature. Remarkably, our analysis uncovered that RAS pathway activation is exceedingly common in human RMS. We also created a new transgenic coinjection methodology to fluorescently label distinct subpopulations of tumor cells based on muscle differentiation status. In conjunction with fluorescent activated cell sorting, cell transplantation, and limiting dilution analysis, we were able to identify the cancer stem cell in zebrafish ERMS. When coupled with gene expression studies of this cell population, we propose that the zebrafish RMS cancer stem cell shares similar self- renewal programs as those found in activated satellite cells.