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.

Automated summary

The HER2 mutations or amplifications are found in 7% of colon cancers, often co-occurring with mutations in genes like APC. Research shows that HER2(V777L) promotes cellular proliferation in the intestinal epithelium, and when combined with APC mutations, they further enhance proliferation of intestinal crypts.