# Project 1: Effect of Iron Deprivation on H. pylori-induced Gastric Carcinogenesis

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $337,818

## Abstract

Project 1 Summary
H. pylori is the strongest known risk factor for gastric cancer. One H. pylori determinant that augments cancer
risk is the cag type IV secretion system (T4SS) which exports an oncoprotein, CagA, into host epithelial cells. A
host molecule that influences gastric cancer in conjunction with H. pylori is ß-catenin, which tightly regulates
stem cell homeostasis; correspondingly, aberrant ß-catenin signaling within a susceptible stem cell population
may lower the threshold for carcinogenesis. A specific stem cell marker in the stomach is Leucine-rich repeats
and immunoglobulin-like domains 1 (Lrig1), a pan-ERBB regulator, and targeted activation of ß-catenin within
Lrig1+ cells leads to the development of hyperplasia, hyperproliferation, and high-grade dysplasia in the
stomach. Our group has now infected mouse and human gastroids to demonstrate that H. pylori can activate ß-
catenin and drive proliferation, expansion, and functional activation of Lrig1+ cells in a cag T4SS-dependent
manner. Another cag T4SS-dependent carcinogenic response occurs within the context of iron deficiency and
we have shown that iron depletion enhances the ability of H. pylori to colonize the gastric stem cell niche, to
activate ß-catenin, and induce injury in mice. In studies performed with Core A, we demonstrated that iron
depletion accelerates carcinogenesis in H. pylori-infected Mongolian gerbils in a cagA-dependent manner. With
Project 3, we demonstrated that H. pylori harvested from iron-deficient gerbils exhibit an enhanced capacity to
assemble cag T4SS-associated pili, translocate CagA, and induce expression of proinflammatory cytokines.
Proteomics and metabolomics studies performed with Cores B and C and whole genome sequencing
performed with Projects 2 and 3 have identified a focused subset of differentially expressed proteins,
metabolites, and genetic mutations, respectively, among H. pylori strains isolated from iron-deficient versus
iron-normal gerbils as well as humans with premalignant lesions. Our hypothesis is that specific interactions
between H. pylori and Lrig1 progenitor cells contribute to augmentation in cancer risk conferred by cag+ strains
within the context of iron deficiency. Thus, our specific aims are to:
1. Utilize mouse models and gastroids to define the role of Lrig1 and new effectors in regulating
 oncogenic epithelial responses to H. pylori cag+ carcinogenic strains.
2. Define the role of iron deficiency and Lrig1 in pathogenesis using H. pylori-infected gastroids and ß-
 catenin over-expressing mouse models.
3. Utilize rodent models and H. pylori mutant strains to inform mechanistic studies focused on microbial
 virulence constituents within the context of iron deficiency.
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## Key facts

- **NIH application ID:** 9883728
- **Project number:** 5P01CA116087-13
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** RICHARD M. PEEK
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,818
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883728

## Citation

> US National Institutes of Health, RePORTER application 9883728, Project 1: Effect of Iron Deprivation on H. pylori-induced Gastric Carcinogenesis (5P01CA116087-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9883728. Licensed CC0.

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