# Project 2: EGFR, ODC, and the Hypusome in H. pylori-induced Gastric Cancer

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $326,687

## Abstract

PROJECT 2 SUMMARY
Half of the global population harbors H. pylori infection, the strongest known risk factor for gastric cancer,
which is the third leading cause of cancer deaths worldwide. Continued immigration of infected persons
ensures that H. pylori infection will remain a major disease burden in the U.S. Antibiotics do not uniformly
eradicate the infection, and exert only a modest effect on cancer risk. H. pylori-induced cancer development is
driven by chronic active gastritis. Project 2 will elucidate novel mechanisms underlying gastric inflammation
and downstream carcinogenesis, and will translate these results to humans. During the award period we
collaborated with the other Projects and the Cores to address why the host immune response fails to eliminate
the pathogen, and, instead, causes gastritis and cancer. Key discoveries included: 1) Epidermal growth factor
receptor (EGFR) activation (phosphorylation) occurs in gastric epithelial cells (GECs) during chronic gastritis
and intestinal metaplasia, while pEGFR in gastric macrophages is elevated from gastritis to the endpoint of
cancer; 2) EGFR signaling regulates macrophage activation patterns: mice that we generated with myeloid-
specific deletion of Egfr exhibited marked attenuation of M1 macrophage responses, MyD88, MAPK1/3, and
NF-κB activation, chemokine expression, and Th1 and Th17 responses, but enhanced Treg response; 3) The
EGFR inhibitor, gefitinib, reduces gastric cancer in H. pylori-infected INS-GAS mice or gerbils; 4) Inhibition of
ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine synthesis, blocks gastric cancer in
gerbils, and mice we generated with myeloid-specific deletion of Odc had increased M1 macrophage
responses to H. pylori and reduced colonization; this was due to elimination of immunosuppressive effects of
the polyamine putrescine, which blocks transcription through histone modifications; 5) Formation of hypusine
from the polyamine spermidine by deoxyhypusine synthase (DHPS) is upregulated by H. pylori and leads to
targeted translation of mRNAs encoding for pro-inflammatory proteins specifically in macrophages, constituting
what we have termed “The Hypusome”; 6) EGFR signaling is linked to ODC levels during H. pylori infection,
providing substrate for hypusination. These insights reveal previously unknown effects of macrophages in
gastric carcinogenesis. Our hypothesis is that EGFR, ODC, and hypusination form an inter-related axis in
gastric macrophages that leads to H. pylori-induced immune dysregulation, inflammation, and gastric
carcinoma. We will benefit from the tight integration in this PPG to address our Aims, which are to determine
the role of the following in H. pylori-induced inflammation-associated gastric carcinogenesis: 1) EGFR
activation and downstream signaling; 2) ODC; 3) Hypusination/DHPS. This will be accomplished with cell-
specific gene deletion and inhibitors in mouse and gerbil cancer models with validation in human tiss...

## Key facts

- **NIH application ID:** 9883729
- **Project number:** 5P01CA116087-13
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Keith T. Wilson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,687
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883729

## Citation

> US National Institutes of Health, RePORTER application 9883729, Project 2: EGFR, ODC, and the Hypusome in H. pylori-induced Gastric Cancer (5P01CA116087-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9883729. Licensed CC0.

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