胃肠化生（GIM）代表癌前阶段，其特征是胃粘膜的形态和病理生理变化，其中胃上皮细胞转变为类似于肠细胞的表型。先前的研究表明，N-甲基-N'-硝基-N-亚硝基胍（MNNG）灌胃可诱发小鼠胃癌和肠化生。在这里，我们证明 MNNG 在三维 (3D) 小鼠类器官中诱导 GIM。我们的组织学分析表明，MNNG 诱导的胃类器官经历了经典的形态学改变，表现出 CDX2 和 MUC2 的明显上调，以及 ATP4B 和 MUC6 的下调。重要的是，在 MNNG 处理的类器官中观察到的化生细胞源自 MIST1 细胞，表明其胃主细胞谱系。功能分析表明，RAS 信号通路的激活可驱动 MNNG 诱导的 3D 类器官化生，反映了在人类 GIM 中观察到的特征。因此，使用 3D 类器官对肠化生进行建模，为了解胃粘膜内肠化生发育过程中胃上皮谱系的分子机制和时空动态提供了宝贵的见解。我们的结论是，利用 3D 类器官的 MNNG 诱导化生模型为制定预防和治疗策略提供了一个强大的平台，以在癌前病变发生之前降低胃癌的风险。© 作者 2024。由牛津大学出版社代表中国科学院上海生命科学研究院生物化学与细胞生物学研究所。

Gastric intestinal metaplasia (GIM) represents a precancerous stage characterized by morphological and pathophysiological changes in the gastric mucosa, where gastric epithelial cells transform into a phenotype resembling that of intestinal cells. Previous studies have demonstrated that the intragastric administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces both gastric carcinoma and intestinal metaplasia in mice. Here, we show that MNNG induces GIM in three-dimensional (3D) mouse organoids. Our histological analyses reveal that MNNG-induced gastric organoids undergo classical morphological alterations, exhibiting a distinct up-regulation of CDX2 and MUC2, along with a down-regulation of ATP4B and MUC6. Importantly, metaplastic cells observed in MNNG-treated organoids originate from MIST1+ cells, indicating their gastric chief cell lineage. Functional analyses show that activation of the RAS signaling pathway drives MNNG-induced metaplasia in 3D organoids, mirroring the characteristics observed in human GIM. Consequently, modeling intestinal metaplasia using 3D organoids offers valuable insights into the molecular mechanisms and spatiotemporal dynamics of the gastric epithelial lineage during the development of intestinal metaplasia within the gastric mucosa. We conclude that the MNNG-induced metaplasia model utilizing 3D organoids provides a robust platform for developing preventive and therapeutic strategies to mitigate the risk of gastric cancer before precancerous lesions occur.© The Author(s) 2024. Published by Oxford University Press on behalf of Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.