Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts
Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts
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DOI：
10.1007/s00401-014-1297-8
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发表时间：
2014-07-01
影响因子：
12.7
通讯作者：
Schueller, Ulrich
中科院分区：
文献类型：
--
作者：
Poeschl, Julia;Stark, Sebastian;Schueller, Ulrich
髓母细胞瘤是一种恶性胚胎性脑瘤，预后极不稳定。为了研究这种肿瘤的生物学和进行临床前治疗研究，人们已经在产生合适的小鼠模型上投入了大量的努力。然而，随着人类髓母细胞瘤亚型的进展，这些模型的使用已经变得有争议。这项研究综合了多个相关的小鼠模型，并将140只小鼠肿瘤和423例人髓母细胞瘤的基因变化和基因表达数据进行了全球匹配。通过AGDEX分析和k-均值聚类，我们发现BlBP-cre：：CTNNB1(Ex3)(F1/+)TrP53(F1/F1)小鼠模型非常适合于人WNT髓母细胞瘤，并且在各种基于Myc或Mycn的小鼠髓母细胞瘤中，GLT1-TTA：：TrE-MYCN/Luc小鼠的肿瘤被证明是对人类第3组髓母细胞瘤最特异的。没有一个分析模型显示与第4组肿瘤有显著匹配。有趣的是，携带ptch1或Smo突变的小鼠有选择地模拟成年龄段的SHH髓母细胞瘤，尽管这种突变在所有人类年龄段都有发生。因此，我们认为SHH-MBS的婴儿或成人基因表达模式并不完全由特定的突变决定。Ptch1突变的人髓母细胞瘤与同一年龄组的ptch1野生型肿瘤比与其他年龄组的ptch1突变的肿瘤显示出更多的相似之处，这支持了这一点。总之，我们对以前未知的不同模型的特异性提供了新的见解，并建议将这些发现作为选择合适的模型进行髓母细胞瘤临床前研究的坚实基础。
Medulloblastoma is a malignant embryonal brain tumor with highly variable outcome. In order to study the biology of this tumor and to perform preclinical treatment studies, a lot of effort has been put into the generation of appropriate mouse models. The usage of these models, however, has become debatable with the advances in human medulloblastoma subgrouping. This study brings together multiple relevant mouse models and matches genetic alterations and gene expression data of 140 murine tumors with 423 human medulloblastomas in a global way. Using AGDEX analysis and k-means clustering, we show that the Blbp-cre::Ctnnb1(ex3) (Fl/+) Trp53 (Fl/Fl) mouse model fits well to human WNT medulloblastoma, and that, among various Myc- or Mycn-based mouse medulloblastomas, tumors in Glt1-tTA::TRE-MYCN/Luc mice proved to be most specific for human group 3 medulloblastoma. None of the analyzed models displayed a significant match to group 4 tumors. Intriguingly, mice with Ptch1 or Smo mutations selectively modeled SHH medulloblastomas of adulthood, although such mutations occur in all human age groups. We therefore suggest that the infantile or adult gene expression pattern of SHH MBs are not solely determined by specific mutations. This is supported by the observation that human medulloblastomas with PTCH1 mutations displayed more similarities to PTCH1 wild-type tumors of the same age group than to PTCH1-mutated tumors of the other age group. Together, we provide novel insights into previously unrecognized specificity of distinct models and suggest these findings as a solid basis to choose the appropriate model for preclinical studies on medulloblastoma.