Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease

Abstract

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 that faithfully recapitulate different subtypes of the human disease. To close this gap, we developed methods to somatically introduce different oncogenic lesions directly into the stomach epithelium and show that genotypic configurations observed in patients produce metastatic gastric cancers that recapitulate the histological, molecular, and clinical features of all non-viral molecular subtypes of the human disease. Applying this platform to both wild-type and immune-deficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells that produced distinct patterns of metastasis that were mirrored in patients. Our results establish and credential a highly portable platform for producing autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts aimed at improving outcomes in gastric cancer patients.

Early Immune Remodeling Steers Clinical Response to First-Line Chemoimmunotherapy in Advanced Gastric Cancer

“…Preclinical models to functionalize the study of immune TME manipulation remains a problem in immunomodulatory drug development, including GEA ( 84–86 ). We had intentionally structured our trial with serial timepoints to partly address this limitation and enhance confidence in our observations and we hope the future work with improved model systems can test some of our observations ( 87 ). We note that the focus of our work is for hypothesis generation for future studies and future work may expand on the number of patients analyzed.…”

Sequential pembrolizumab cooperates with platinum/5FU to remodel the tumor microenvironment in advanced gastric cancer: a phase II chemoimmunotherapy trial

“…Pre-clinical models to functionalize the study of immune TME manipulation remains a problem in immunomodulatory drug development, including GEA [89][90][91] . We had intentionally structured our trial with serial timepoints to partly address this limitation and enhance confidence in our observations and we hope the future work with improved models can test some of our observations 92 . In addition, the focus of our work is on the immune interaction networks and detailed analyses incorporating tumor genetics, neoantigen prediction, and T cell receptor sequences are beyond the scope of this manuscript but remain areas of interest.…”