Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.

转移性胃癌是一种高度致命的癌症，对传统和分子靶向治疗反应不佳。尽管具有临床相关性，但人们对这种疾病的行为和治疗反应背后的机制知之甚少，部分原因是缺乏可处理的模型。在这里，我们开发了将不同的致癌病变直接引入小鼠胃上皮的方法。在产生转移性胃癌的患者中观察到的基因型配置概括了人类疾病所有非病毒分子亚型的组织学、分子和临床特征。将这个平台应用于野生型和免疫缺陷小鼠，揭示了转移细胞的基因型、趋器官性和免疫监视之间以前未被认识到的联系，这产生了在患者身上反映出来的不同转移模式。我们的研究结果建立了一个高度可移植的平台，用于生成具有灵活基因型和宿主背景的本土癌症模型，这可以揭示胃肿瘤发生机制或测试新的治疗概念。