Assessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids
Assessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids
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DOI：
10.1038/s41467-020-16432-0
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发表时间：
2020-05-27
影响因子：
16.6
通讯作者：
Clevers, Hans
中科院分区：
文献类型：
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作者：
Lohmussaar, Kadi;Kopper, Oded;Clevers, Hans
高级别浆液性卵巢癌（HG-SOC）-通常被称为“沉默的杀手”-是最致命的妇科恶性肿瘤。输卵管（小鼠输卵管）和卵巢表面上皮（OSE）被认为是这种癌症起源的主要候选组织。然而，各组织对HG-SOC的相对贡献尚不清楚。在这里，我们从小鼠输卵管和OSE组织建立了HG-SOC的基于类器官的肿瘤进展模型。我们使用CRISPR-Cas9基因组编辑将突变引入HG-SOC中常见的突变基因，如Trp 53，Brca 1，Nf 1和Pten。我们的研究结果支持HG-SOC的双重起源假说，因为我们证明了两种上皮细胞都可以引起具有高级别病理学的卵巢肿瘤。然而，突变的输卵管类器官在体外扩张得更快，并且在移植后更容易形成恶性肿瘤。此外，体外药物测试揭示了对用于治疗患者HG-SOC的常见药物的不同谱系依赖性敏感性。输卵管（FT）或卵巢表面上皮（OSE）对高级别浆液性卵巢癌（HG-SOC）发展的相对贡献尚不清楚。在这里，作者从小鼠输卵管和OSE组织中建立了类器官模型，允许通过CRISPR-Cas9基因组编辑进行癌症建模，并报告了小鼠HG-SOC的双重起源。
High-grade serous ovarian cancer (HG-SOC)-often referred to as a "silent killer"-is the most lethal gynecological malignancy. The fallopian tube (murine oviduct) and ovarian surface epithelium (OSE) are considered the main candidate tissues of origin of this cancer. However, the relative contribution of each tissue to HG-SOC is not yet clear. Here, we establish organoid-based tumor progression models of HG-SOC from murine oviductal and OSE tissues. We use CRISPR-Cas9 genome editing to introduce mutations into genes commonly found mutated in HG-SOC, such as Trp53, Brca1, Nf1 and Pten. Our results support the dual origin hypothesis of HG-SOC, as we demonstrate that both epithelia can give rise to ovarian tumors with high-grade pathology. However, the mutated oviductal organoids expand much faster in vitro and more readily form malignant tumors upon transplantation. Furthermore, in vitro drug testing reveals distinct lineage-dependent sensitivities to the common drugs used to treat HG-SOC in patients. The relative contribution of fallopian tube (FT) or ovarian surface epithelium (OSE) to high-grade serous ovarian cancer (HG-SOC) development is unclear. Here, the authors establish organoid models from murine oviductal and OSE tissues that allow cancer modeling via CRISPR-Cas9 genome editing, and report a dual origin of murine HG-SOC.