Ovarian cancer is the most lethal gynecologic cancer to date. High-grade serous ovarian carcinoma (HGSOC) accounts for most ovarian cancer cases, and it is most frequently diagnosed at advanced stages. Here, we developed a novel strategy to generate somatic ovarian cancer mouse models using a combination of in vivo electroporation and CRISPR-Cas9–mediated genome editing. Mutation of tumor suppressor genes associated with HGSOC in two different combinations ( Brca1, Tp53, Pten with and without Lkb1) resulted in successfully generation of HGSOC, albeit with different latencies and pathophysiology. Implementing Cre lineage tracing in this system enabled visualization of peritoneal micrometastases in an immune-competent environment. In addition, these models displayed copy number alterations and phenotypes similar to human HGSOC. Because this strategy is flexible in selecting mutation combinations and targeting areas, it could prove highly useful for generating mouse models to advance the understanding and treatment of ovarian cancer. Significance: This study unveils a new strategy to generate genetic mouse models of ovarian cancer with high flexibility in selecting mutation combinations and targeting areas.

中文翻译：

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结合体内输卵管电穿孔和 CRISPR-Cas9 介导的基因组编辑对高级别浆液性卵巢癌进行建模

卵巢癌是迄今为止最致命的妇科癌症。高级别浆液性卵巢癌 (HGSOC) 占大多数卵巢癌病例，并且最常在晚期诊断。在这里，我们开发了一种新策略，结合体内电穿孔和 CRISPR-Cas9 介导的基因组编辑来生成体细胞卵巢癌小鼠模型。两种不同组合（Brca1、Tp53、Pten 有和没有 Lkb1）中与 HGSOC 相关的肿瘤抑制基因的突变导致成功产生 HGSOC，尽管具有不同的潜伏期和病理生理学。在该系统中实施 Cre 谱系追踪可以在免疫能力强的环境中实现腹膜微转移的可视化。此外，这些模型显示出与人类 HGSOC 相似的拷贝数改变和表型。由于这种策略在选择突变组合和靶向区域方面非常灵活，因此它可以证明对生成小鼠模型以促进对卵巢癌的理解和治疗非常有用。意义：这项研究揭示了一种新的策略，可以生成卵巢癌的遗传小鼠模型，在选择突变组合和靶向区域方面具有高度的灵活性。