HER2 and APC Mutations Promote Altered Crypt-Villus Morphology and Marked Hyperplasia in the Intestinal Epithelium

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.