Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research

Paul W Tetteh, Kai Kretzschmar, Harry Begthel, Maaike van den Born, Jeroen Korving, Folkert H M Morsink, Henner Farin, Johan H van Es, G Johan A Offerhaus, Hans Clevers

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1(CreER) knock-in (KI) mouse with broad Cre activity in epithelial cells of the proximal colon and cecum. Deletion of the tumor suppressor gene Apc using the Car1(CreER) KI caused tumor formation in the cecum but did not yield adenomas in the proximal colon. Mutation of both Apc and Kras yielded microadenomas in both the cecum and the proximal colon, which progressed to macroadenomas with significant morbidity. Aggressive carcinomas with some invasion into lymph nodes developed upon combined induction of oncogenic mutations of Apc, Kras, p53, and Smad4 Importantly, no adenomas were observed in the small intestine. Additionally, we observed tumors from differentiated Car1-expressing cells with Apc/Kras mutations, suggesting that a top-down model of intestinal tumorigenesis can occur with multiple mutations. Our results establish the Car1(CreER) KI as a valuable mouse model to study colon-specific tumorigenesis and metastasis as well as cancer-cell-of-origin questions.

Original languageEnglish
Pages (from-to)11859-11864
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number42
DOIs
Publication statusPublished - 18 Oct 2016

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    Tetteh, P. W., Kretzschmar, K., Begthel, H., van den Born, M., Korving, J., Morsink, F. H. M., Farin, H., van Es, J. H., Offerhaus, G. J. A., & Clevers, H. (2016). Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research. Proceedings of the National Academy of Sciences of the United States of America, 113(42), 11859-11864. https://doi.org/10.1073/pnas.1614057113