小鼠模型对于癌症研究具有重要作用，但是关于各种小鼠癌症模型与人类癌症的基因组水平相似之处知之甚少。
2019年7月22日，英国《自然》旗下《自然通讯》在线发表美国密歇根州立大学、国家卫生研究院国家癌症研究所的研究报告，通过小鼠乳腺癌模型综合分析，揭示了与人类疾病的重要相似之处。
该研究完成了两种常用乳腺癌小鼠模型：HER2基因小鼠乳腺病毒模型（MMTV-Neu）和PyMT基因小鼠乳腺病毒模型（MMTV-PyMT）的全基因组测序和转录组分析。结合体外和体内研究表明，胶原蛋白1型α1（COL1A1）和软骨黏附蛋白（CHAD）等关键细胞外基质蛋白质的编码基因拷贝数量改变，可以引起这些小鼠模型的乳腺癌转移。除了拷贝数量改变之外，还观察到肿瘤倾向于通过MMTV-PyMT小鼠模型的受体型酪氨酸蛋白磷酸酶H（PTPRH）等磷酸酶编码基因突变，对酪氨酸激酶参与的信号转导进行调控。PTPRH突变可以引起磷酸化表皮生长因子受体（EGFR）表达水平提高以及肿瘤潜伏时间缩短。
因此，该研究结果表明，掌握小鼠模型的完整基因组特征十分重要，对于认识人类癌症非常实用。
Nat Commun. 2019 Jul 22. [Epub ahead of print]
Integrated analyses of murine breast cancer models reveal critical parallels with human disease.
Jonathan P. Rennhack, Briana To, Matthew Swiatnicki, Caleb Dulak, Martin P. Ogrodzinski, Yueqi Zhang, Caralynn Li, Evan Bylett, Christina Ross, Karol Szczepanek, William Hanrahan, Muthu Jayatissa, Sophia Y. Lunt, Kent Hunter, Eran R. Andrechek.
Michigan State University, East Lansing, MI, USA; National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Mouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level. Here, we complete whole genome sequencing and transcriptome profiling of two widely used mouse models of breast cancer, MMTV-Neu and MMTV-PyMT. Through integrative in vitro and in vivo studies, we identify copy number alterations in key extracellular matrix proteins including collagen 1 type 1 alpha 1 (COL1A1) and chondroadherin (CHAD) that drive metastasis in these mouse models. In addition to copy number alterations, we observe a propensity of the tumors to modulate tyrosine kinase-mediated signaling through mutation of phosphatases such as PTPRH in the MMTV-PyMT mouse model. Mutation in PTPRH leads to increased phospho-EGFR levels and decreased latency. These findings underscore the importance of understanding the complete genomic landscape of a mouse model and illustrate the utility this has in understanding human cancers.
DOI: 10.1038/s41467-019-11236-3
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