Construction and application of a genetically engineered mouse model of gastric adenocarcinoma.

Abstract

BACKGROUND: The lack of specific and immunocompetent gastric cancer models has hindered the exploration of gastric adenocarcinoma (GAC). We constructed a spontaneous and transplantable GAC model using a genetically engineered mouse. METHODS: We generated a tamoxifen-inducible CRISPR-based Anxa10-CreERT2 mouse line and crossed it with the KrasG12D/+ and Tp53R172H/+ strains to develop Anxa10-CreERT2; KrasG12D/+; Tp53R172H/+ mice on a C57BL/6J background. Tamoxifen and N-methyl-N-nitrosourea were administered to induce in situ tumor development. An orthotopic gastric tumor was confirmed by histological analysis and positron emission tomography/computed tomography. A transplantable mouse-derived allograft (MDA) model and stable GAC cell line (ST-YC19) were subsequently established using MDA. The malignant characteristics and drug responses were evaluated. RESULTS: Spontaneous GAC had a 100% incidence within 2.5 months, was predominantly of the intestinal type, and presented essential molecular features of the CIN subtype. The ST-YC19 GAC cell line derived from MDAs exhibited an aggressive phenotype, robust tumorigenic potential, peritoneal dissemination, and distant metastasis. This model showed limited sensitivity to anti-programmed death-1 immunotherapy. CONCLUSION: We successfully established a spontaneous GAC model and its corresponding cell line in C57BL/6J mice, enabling a comprehensive investigation of tumor progression, metastasis, therapeutic response, and resistance mechanisms in vivo. This model represents a valuable platform for advancing precision medicine in gastric cancer.