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

Authors
  • Murray, Elisa1
  • Cheng, Xiaoqing2
  • Krishna, Anagha2
  • Jin, Xiaohua2
  • Ohara, Takahiro E3
  • Stappenbeck, Thaddeus S4
  • Bose, Ron5
  • 1 Division of Biology and Biomedical Sciences, Department of Biochemistry, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
  • 2 Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
  • 3 Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
  • 4 Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • 5 Division of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri; Alvin J. Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri. Electronic address: [email protected]
Type
Published Article
Journal
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier
Publication Date
Apr 27, 2021
Identifiers
DOI: 10.1016/j.jcmgh.2021.04.012
PMID: 33930605
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. We generated a HER2 transgenic mouse (HER2V777L Tg) possessing an activating mutation commonly found in colorectal cancer patients, HER2V777L, using transcription activator-like effector nucleases-based gene editing technology. We expressed the HER2V777L transgene in mouse small intestine and colon using Lgr5-Cre and Villin-Cre recombinases. In addition, we analyzed Lgr5-Cre; APCmin; HER2V777L Tg mice by morphologic and gene expression assays on intestinal sections and organoids derived from the epithelium. HER2V777L 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. HER2V777L expression in the context of APC loss resulted in further enhancement and expansion of the proliferative crypt compartment. We established an epithelial intrinsic role for HER2V777L on enhanced cellular proliferation. Additionally, we determined that HER2 and APC mutations, when combined, promote enhanced proliferation of intestinal crypts. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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