Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA.
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, 48824, USA.
Nat Commun. 2019 Jul 22;10(1):3261. doi: 10.1038/s41467-019-11236-3.
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.
小鼠模型在癌症研究中具有重要作用，但对于各种模型在基因组水平上与人类癌症的相似程度知之甚少。在这里，我们完成了两种广泛使用的乳腺癌小鼠模型 MMTV-Neu 和 MMTV-PyMT 的全基因组测序和转录组分析。通过体外和体内的综合研究，我们确定了关键细胞外基质蛋白（包括胶原蛋白 1 型 alpha 1 （COL1A1）和软骨粘连蛋白（CHAD））中的拷贝数改变，这些改变会导致这些小鼠模型中的转移。除了拷贝数改变外，我们还观察到这些肿瘤倾向于通过突变如 MMTV-PyMT 小鼠模型中的磷酸酶 PTPRH 来调节酪氨酸激酶介导的信号通路。PTPRH 的突变导致磷酸化 EGFR 水平增加和潜伏期缩短。这些发现强调了了解小鼠模型完整基因组景观的重要性，并说明了这对理解人类癌症的实用性。
