Loss of Lrig1 Leads to Expansion of Brunner Glands Followed by Duodenal Adenomas with Gastric Metaplasia
Open accessAbstract
Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-ErbB negative regulator and intestinal stem cell marker down-regulated in many malignancies. We previously reported that 14 of 16 Lrig1-CreERT2/CreERT2 (Lrig1(-/-)) mice developed duodenal adenomas, providing the first in vivo evidence that Lrig1 acts as a tumor suppressor. We extended this study to a larger cohort and found that 49 of 54 Lrig1(-/-) mice develop duodenal adenomas beginning at 3 months. Most adenomas were histologically low grade and overlaid expanded Brunner glands. There was morphologic and biochemical blurring of the boundary between the epithelium and Brunner glands with glandular coexpression of ErbB2, which is normally restricted to the epithelium, and the Brunner gland marker Mucin6. Some adenomas were high grade with reduced Brunner glands. At age 4 to 5 weeks, before adenoma formation, we observed enhanced proliferation in Brunner glands and, at 2 months, an increase in the size of the Brunner gland compartment. Elevated expression of the epidermal growth factor receptor (Egfr) ligands amphiregulin and β-cellulin, as well as Egfr and phosphorylated Egfr, was detected in adenomas compared with adjacent normal tissue. These adenomas expressed the gastric-specific genes gastrokine1 and mucin5ac, indicating gastric metaplasia. Moreover, we found that a subset of human duodenal tumors exhibited features of LRIG1(-/-) adenomas, including loss of LRIG1, gastric metaplasia (MUCIN5AC and MUCIN6), and increased amphiregulin and Egfr activity.
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Depletion of tumor suppressor LRIG1 was identified as the top hit contributing to increased cell proliferation.
“Notably, the depletion of tumor suppressor LRIG1, a negative regulator of ERBB receptor tyrosine kinases40–42, was identified as the top hit contributing to increased cell proliferation (Fig. 1D).”
From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [41]
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- Authors
- Wang, Y., Shi, C., Lu, Y., Poulin, E. J., Franklin, J. L., & Coffey, R. J.
- Affiliations
- Vanderbilt University Medical Center (US)
- Nashville VA Medical Center (US)
- Corresponding author
- Coffey, Robert J.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 185
- Issue
- 4
- Pages
- 1123-1134
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC4380843
- OpenAlex
- W2113581487
- Cited by
- 26
- References
- 40
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 2
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- Vanderbilt University Medical Center (P30DK058404)
- National Institutes of Health
- National Cancer Institute (CA151566, CA46413, R01CA151566, P50CA095103, R01CA046413)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK058404)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Keywords
- Lrig1, duodenal adenoma, gastric metaplasia, Brunner glands, ERBB2, epidermal growth factor receptor, amphiregulin, tumor suppressor, intestinal stem cells, duodenal neoplasms
- MeSH terms
- Adenoma, Animals, Brunner Glands, Duodenal Neoplasms, Humans, Ligands, Membrane Glycoproteins, Metaplasia, Mice, Inbred C57BL, Models, Biological, Nerve Tissue Proteins, Stomach, Cell Proliferation, ErbB Receptors
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