| First Author | Murray E | Year | 2021 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 12 |
| Issue | 3 | Pages | 1105-1120 |
| PubMed ID | 33930605 | Mgi Jnum | J:314240 |
| Mgi Id | MGI:6817623 | Doi | 10.1016/j.jcmgh.2021.04.012 |
| Citation | Murray E, et al. (2021) HER2 and APC Mutations Promote Altered Crypt-Villus Morphology and Marked Hyperplasia in the Intestinal Epithelium. Cell Mol Gastroenterol Hepatol 12(3):1105-1120 |
| abstractText | BACKGROUND AND AIMS: The Cancer Genome Atlas (TCGA) project has identified HER2 mutations or amplification in 7% of colon cancers. In addition to HER2 mutations, colon cancer patients also possess co-occurring mutations in genes such as APC. Here, we investigated the role of HER2 and APC mutations on the crypt-villus architecture of the intestinal epithelium, localization of secretory cells, and expression of intestinal stem cell markers. METHODS: We generated a HER2 transgenic mouse (HER2(V777L) Tg) possessing an activating mutation commonly found in colorectal cancer patients, HER2(V777L), using transcription activator-like effector nucleases-based gene editing technology. We expressed the HER2(V777L) transgene in mouse small intestine and colon using Lgr5-Cre and Villin-Cre recombinases. In addition, we analyzed Lgr5-Cre; APC(min); HER2(V777L) Tg mice by morphologic and gene expression assays on intestinal sections and organoids derived from the epithelium. RESULTS: HER2(V777L) expression resulted in hypertrophic crypt formation with expanded zones of proliferation. Proximal intestinal villi showed increased abundance of multiple differentiated lineages including extensive intermediate cell differentiation, as evidenced by MUC2/MMP7 co-immunofluorescence and transmission electron microscopy. HER2(V777L) expression in the context of APC loss resulted in further enhancement and expansion of the proliferative crypt compartment. CONCLUSIONS: We established an epithelial intrinsic role for HER2(V777L) on enhanced cellular proliferation. Additionally, we determined that HER2 and APC mutations, when combined, promote enhanced proliferation of intestinal crypts. |
