Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and UMC Utrecht, Utrecht, The Netherlands.
Oncode Institute, Utrecht, The Netherlands.
Nat Commun. 2020 May 27;11(1):2660. doi: 10.1038/s41467-020-16432-0.
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.
高级别浆液性卵巢癌（HG-SOC）-通常被称为“沉默杀手”-是最致命的妇科恶性肿瘤。输卵管（鼠输卵管）和卵巢表面上皮（OSE）被认为是这种癌症的主要候选起源组织。然而，每种组织对 HG-SOC 的相对贡献尚不清楚。在这里，我们从鼠输卵管和 OSE 组织中建立了基于类器官的 HG-SOC 肿瘤进展模型。我们使用 CRISPR-Cas9 基因组编辑将常见于 HG-SOC 中突变的基因（如 Trp53、Brca1、Nf1 和 Pten）引入到基因中。我们的结果支持 HG-SOC 的双重起源假说，因为我们证明上皮都可以产生具有高级别病理的卵巢肿瘤。然而，突变的输卵管类器官在体外生长更快，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 的常见药物的独特的谱系依赖性敏感性。
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