Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Germany; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Germany.
Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Germany; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Germany; Department of Medicine II, TUM School of Medicine, Technische Universität München, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Curr Opin Genet Dev. 2019 Feb;54:88-96. doi: 10.1016/j.gde.2019.04.001. Epub 2019 May 9.
Gene targeting in mammals has revolutionized the study of complex diseases, involving the interaction of multiple genes, cells, and organ systems. In cancer, genetically engineered mouse models deciphered biological principles by integrating molecular mechanisms, cellular processes, and environmental signals. Major advances in manipulative mouse genetics are currently emerging from breakthroughs in gene editing, which open new avenues for rapid model generation. Here, we review recent developments in engineering CRISPR mouse models of cancer. We describe engineering strategies, including germline manipulation of zygotes or embryonic stem cells, direct in vivo somatic gene editing, and ex vivo targeting of cellular transplant models. We also discuss promises and limitations of the expanding spectrum of CRISPR applications, ranging from engineering of simple mutations over complex genomic rearrangements to gene and epigenome regulation. Fast and scalable in vivo CRISPR methodologies pave the way for a new phase of functional cancer genomics.
哺乳动物的基因靶向技术已经彻底改变了复杂疾病的研究，涉及多个基因、细胞和器官系统的相互作用。在癌症中，通过整合分子机制、细胞过程和环境信号，基因工程小鼠模型揭示了生物学原理。基因编辑方面的突破为快速模型生成开辟了新途径，目前正在推动操纵小鼠遗传学方面的重大进展。在这里，我们回顾了癌症 CRISPR 小鼠模型工程的最新进展。我们描述了工程策略，包括对受精卵或胚胎干细胞进行种系操作、直接体内体细胞基因编辑以及细胞移植模型的体外靶向。我们还讨论了不断扩展的 CRISPR 应用范围的前景和局限性，从简单突变的工程到复杂基因组重排，再到基因和表观基因组调控。快速和可扩展的体内 CRISPR 方法为功能癌症基因组学的新阶段铺平了道路。
