Probing the tumorigenic potential of genetic interactions reconstituted in murine fallopian tube organoids
Probing the tumorigenic potential of genetic interactions reconstituted in murine fallopian tube organoids
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DOI：
10.1002/path.5752
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发表时间：
2021-07-21
影响因子：
7.3
通讯作者：
Hippo, Yoshitaka
中科院分区：
文献类型：
--
作者：
Maru, Yoshiaki;Tanaka, Naotake;Hippo, Yoshitaka
基因工程小鼠一直是肿瘤发展模型的金标准。最近的研究表明，基因工程类器官可以在免疫功能低下的小鼠中发展皮下肿瘤，至少对于那些偏好主要驱动突变的器官来说是如此。为了进一步证实这一概念，输卵管（FT），卵巢高级别浆液性癌（HGSC）的主要起源细胞，几乎总是携带TP 53突变，研究了p53失活驱动的肿瘤发生。接受慢病毒Cre介导的Trp 53缺失的小鼠FT类器官未发生肿瘤。然而，随后抑制Pten和同时诱导突变Pik 3ca分别导致原位癌和HGSC样肿瘤的发展，而同时缺失Apc导致良性囊肿的发展，反映了PI 3 K/AKT轴的频繁激活和HGSC中Wnt途径激活的边缘影响。与HGSC中RAS途径的频繁激活一致，突变型Kras与Trp 53缺失合作用于肿瘤的发展，尽管接种的类器官的上皮起源，但肿瘤除了癌细胞之外还意外地含有肉瘤细胞。这一发现与先前研究中报道的具有相同基因型的胃肠道类器官的排他性腺癌发展形成鲜明对比，表明组织特异性上皮-间充质转化程序。在肿瘤源性类器官中，Cre介导的Trp 53重组率达到100%，但其他基因未达到100%，这突出了p53失活在FT肿瘤发生中的优势。表达突变Kras的Trp 53野生型FT类器官分别在Cdkn 2a抑制和Tgfbr 2缺失后发展为肉瘤和癌，揭示了新的促肿瘤遗传合作和TGF-β信号传导在FT衍生的肿瘤发生中对上皮-间充质转化的关键作用。总的来说，基于类器官的方法代表了肿瘤发生的捷径，并为肿瘤发生的基因型，细胞类型和肿瘤表型之间的关系提供了新的见解。(c)2021年英国和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Genetically engineered mice have been the gold standard in modeling tumor development. Recent studies have demonstrated that genetically engineered organoids can develop subcutaneous tumors in immunocompromised mice, at least for organs that prefer predominant driver mutations for tumorigenesis. To further substantiate this concept, the fallopian tube (FT), a major cell of origin of ovarian high-grade serous carcinoma (HGSC), which almost invariably carries TP53 mutations, was investigated for p53 inactivation-driven tumorigenesis. Murine FT organoids subjected to lentiviral Cre-mediated Trp53 deletion did not develop tumors. However, subsequent suppression of Pten and simultaneous induction of mutant Pik3ca led to the development of carcinoma in situ and HGSC-like tumors, respectively, whereas concurrent deletion of Apc resulted in the development of benign cysts, mirroring frequent activation of the PI3K/AKT axis and the marginal impact of Wnt pathway activation in HGSC. Consistent with the frequent activation of the RAS pathway in HGSC, mutant Kras cooperated with Trp53 deletion for the development of tumors, which unexpectedly contained sarcoma cells in addition to carcinoma cells, despite the epithelial origin of the inoculated organoids. This finding is in sharp contrast with the exclusive adenocarcinoma development from gastrointestinal organoids with the same genotype reported in previous studies, suggesting a tissue-specific epithelial-mesenchymal transition program. In tumor-derived organoids, the Cre-mediated recombination rate reached 100% for Trp53 but not for the other genes, highlighting the advantage of p53 inactivation in FT tumorigenesis. The Trp53 wildtype FT organoids expressing the mutant Kras developed sarcoma and carcinoma upon Cdkn2a suppression and Tgfbr2 deletion, respectively, revealing novel pro-tumorigenic genetic cooperation and critical roles of TGF-beta signaling for epithelial-mesenchymal transition in FT-derived tumorigenesis. Collectively, the organoid-based approach represents a shortcut to tumorigenesis and provides novel insights into the relationships among genotype, cell type, and tumor phenotype underlying tumorigenesis. (c) 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.