Probing the tumorigenic potential of genetic interactions reconstituted in murine fallopian tube organoids

作者：Yoshiaki Maru, N. Tanaka, Yasutoshi Tatsumi, Yuki Nakamura, Ryoji Yao, T. Noda, M. Itami, Y. Hippo · 发表于：Journal of Pathology · 年份：2021 · DOI：10.1002/path.5752 · 被引用次数：14 · 研究领域：Medicine

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....