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

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. Lay Summary: Stomach cancer research has been hindered by the lack of realistic animal models that mimic the growth and response of human tumors to treatments. To address this, we created a new mouse model using genetic engineering to develop stomach cancer spontaneously, similar to that in humans. By activating specific cancer-causing gene changes in mice, tumors formed reliably within 2.5 months. These tumors can be transplanted into healthy mice or grown as cell lines in the laboratory, thereby allowing us to study how cancer spreads and test therapies. The model demonstrated resistance to a widely used immunotherapy (anti-programmed death-1), highlighting its usefulness in exploring why some treatments fail. This breakthrough provides a powerful tool for studying stomach cancer progression, testing new drugs, and personalizing treatments for patients, bringing us closer to achieving better outcomes for this deadly disease.