Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease Journal Article
| Authors: | Leibold, J.; Tsanov, K. M.; Amor, C.; Ho, Y. J.; Sánchez-Rivera, F. J.; Feucht, J.; Baslan, T.; Chen, H. A.; Tian, S.; Simon, J.; Wuest, A.; Wilkinson, J. E.; Lowe, S. W. |
| Article Title: | 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. 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. © The Author(s) 2024. |
| Keywords: | immunohistochemistry; controlled study; treatment response; survival rate; gene mutation; single nucleotide polymorphism; somatic mutation; genetics; clinical feature; histopathology; splenectomy; nonhuman; flow cytometry; cd8+ t lymphocyte; reproducibility; quality control; animal cell; mouse; animal; animals; mice; animal tissue; metastasis; tumor volume; animal experiment; animal model; genetic variability; genotype; pathology; transcriptomics; uvomorulin; histology; ultrasound; carcinogenesis; disease model; liver metastasis; lung metastasis; genetic recombination; xenograft; genomic instability; microsatellite instability; immunoblotting; natural killer cell; stomach cancer; cancer epidemiology; immunological monitoring; tumor growth; disease models, animal; immunosurveillance; k ras protein; stomach carcinoma; stomach neoplasms; immunocompetent cell; stomach tumor; rna extraction; rna sequence; mouse model; molecularly targeted therapy; meloxicam; buprenorphine; transposase; adenomyosis; gene ontology; gastric mucosa; stomach mucosa; stomach epithelium; sanger sequencing; humans; human; article; gastrointestinal epithelium; differential gene expression; whole exome sequencing; gene set enrichment analysis; gene editing; pathway enrichment analysis; gastric metastasis; neoplastic cell transformation |
| Journal Title: | Nature Cancer |
| Volume: | 5 |
| Issue: | 2 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2024-01-01 |
| Start Page: | 315 |
| End Page: | 329 |
| Language: | English |
| DOI: | 10.1038/s43018-023-00686-w |
| PUBMED: | 38177458 |
| PROVIDER: | scopus |
| PMCID: | PMC10899107 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Scott W. Lowe -- Source: Scopus |
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