尽管单核苷酸变异（SNVs）构成了大多数与癌症相关的遗传变化，并已得到全面编目，但关于它们对肿瘤发生和进展的影响几乎一无所知。为了能够对与癌症相关的SNVs进行功能研究，我们开发了一种用于临床和可调控体内碱基编辑的小鼠系统。可诱导的碱基编辑（iBE）小鼠携带一个在体内广泛组织中能够强调地依赖强力霉素诱导表达的单个表达优化的胞嘧啶碱基编辑转基因，其受控于四环素响应元件。结合质粒或合成引导RNA，iBE推动了在肠道、肺和胰腺器官样本中对单个或多个SNVs的高效工程。基因编辑酶活性的时间调控使得在离体和体内可以进行有序的基因组编辑，而直接送达sgRNA至目标组织则有助于生成原位临床癌症模型。© 2023. Copyright所有，由Springer Nature America, Inc.独家许可。

Although single-nucleotide variants (SNVs) make up the majority of cancer-associated genetic changes and have been comprehensively catalogued, little is known about their impact on tumor initiation and progression. To enable the functional interrogation of cancer-associated SNVs, we developed a mouse system for temporal and regulatable in vivo base editing. The inducible base editing (iBE) mouse carries a single expression-optimized cytosine base editor transgene under the control of a tetracycline response element and enables robust, doxycycline-dependent expression across a broad range of tissues in vivo. Combined with plasmid-based or synthetic guide RNAs, iBE drives efficient engineering of individual or multiple SNVs in intestinal, lung and pancreatic organoids. Temporal regulation of base editor activity allows controlled sequential genome editing ex vivo and in vivo, and delivery of sgRNAs directly to target tissues facilitates generation of in situ preclinical cancer models.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.