Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Cancer Lett. 2024 Apr 28;588:216813. doi: 10.1016/j.canlet.2024.216813. Epub 2024 Mar 16.
Rat model of N-nitrosomethylbenzylamine (NMBzA)-induced esophageal squamous cell carcinoma (ESCC) is routinely used to study ESCC initiation, progression and new therapeutic strategies. However, the model is time-consuming and malignant tumor incidences are low. Here, we report the usage of multi-kinase inhibitor sorafenib as a tumor promoter to establish an efficient two-stage NMBzA-induced rat ESCC carcinogenesis model, resulting in increments of tumor incidences and shortened tumor formation times. By establishing the model and applying whole-genome sequencing, we discover that benign papillomas and malignant ESCCs harbor most of the "driver" events found in rat ESCCs (e.g. recurrent mutations in Ras family, the Hippo and Notch pathways and histone modifier genes) and the mutational landscapes of rat and human ESCCs overlap extensively. We generate tumor cell lines derived from NMBzA-induced papillomas and ESCCs, showing that papilloma cells retain more characteristics of normal epithelial cells than carcinoma cells, especially their exhibitions of normal rat cell karyotypes and inabilities of forming tumors in immunodeficient mice. Three-dimensional (3-D) organoid cultures and single cell RNA sequencing (scRNA-seq) indicate that, when compared to control- and papilloma-organoids, ESCC-organoids display salient abnormalities at tissue and single-cell levels. Multi-omic analyses indicate that NMBzA-induced rat ESCCs are accompanied by progressive hyperactivations of the FAT-Hippo-YAP1 axis and siRNA or inhibitors of YAP1 block the growth of rat ESCCs. Taken together, these studies provide a framework of using an effective rat ESCC model to investigate multilevel functional genomics of ESCC carcinogenesis, which justify targeting YAP1 as a therapeutic strategy for ESCC.
N-亚硝甲基苄基胺（NMBzA）诱导的食管鳞状细胞癌（ESCC）大鼠模型常用于研究 ESCC 的起始、进展和新的治疗策略。然而，该模型耗时且恶性肿瘤发生率较低。在这里，我们报告使用多激酶抑制剂索拉非尼作为肿瘤促进剂来建立有效的 NMBzA 诱导的大鼠 ESCC 致癌发生模型，导致肿瘤发生率增加和肿瘤形成时间缩短。通过建立该模型并进行全基因组测序，我们发现良性乳头状瘤和恶性 ESCC 具有大鼠 ESCC 中发现的大多数“驱动”事件（例如 Ras 家族、Hippo 和 Notch 通路以及组蛋白修饰基因的反复突变），并且大鼠和人类 ESCC 的突变景观广泛重叠。我们从 NMBzA 诱导的乳头状瘤和 ESCC 中生成肿瘤细胞系，表明乳头状瘤细胞比癌细胞保留更多正常上皮细胞的特征，尤其是它们表现出正常大鼠细胞染色体核型并且不能在免疫缺陷小鼠中形成肿瘤。三维（3-D）类器官培养和单细胞 RNA 测序（scRNA-seq）表明，与对照和乳头状瘤类器官相比，ESCC 类器官在组织和单细胞水平上表现出明显的异常。多组学分析表明，NMBzA 诱导的大鼠 ESCC 伴随着 FAT-Hippo-YAP1 轴的逐渐过度激活，并且 siRNA 或 YAP1 抑制剂可阻止大鼠 ESCC 的生长。总之，这些研究为使用有效的大鼠 ESCC 模型来研究 ESCC 致癌发生的多层次功能基因组学提供了一个框架，证明靶向 YAP1 是 ESCC 的一种治疗策略。
