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-?B 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 tissues, and innovative use of proteomics/phosphoproteomics, metabolomics, and organoid models. We will break new ground regarding macrophages in gastric carcinogenesis, leading to novel chemoprevention approaches.
PROJECT 2 NARRATIVE Helicobacter pylori is a type of bacteria that infects the stomach of half of the world's human population, and was discovered to be the main cause of stomach cancer, the third leading cause of cancer death worldwide. Benefiting from synergistic interactions with the other projects and highly developed research cores of this Program Project Grant, we will utilize specialized cell and animal model systems and existing human tissue samples to assess novel molecular pathways altered by H. pylori that lead to poorly controlled stomach damage and ultimately, the development of cancer. The long-term goal of our studies is to establish new targeted strategies for prevention of H. pylori-induced gastric cancer. !
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