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 -catenin, which tightly regulates stem cell homeostasis; correspondingly, aberrant -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 -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 - 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 -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 - 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. !

Public Health Relevance

Project 1 Narrative These studies will define bacterial and host factors that influence gastric cancer within the context of iron deficiency. Such findings may help to identify H. pylori-infected persons at high risk for gastric cancer, who thereby warrant therapy. !

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA116087-14
Application #
10103788
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2008-12-01
Project End
2024-02-29
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
14
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Shen, Xi; Liu, Liping; Peek, Richard M et al. (2018) Supplementation of p40, a Lactobacillus rhamnosus GG-derived protein, in early life promotes epidermal growth factor receptor-dependent intestinal development and long-term health outcomes. Mucosal Immunol 11:1316-1328
Mera, Robertino M; Bravo, Luis E; Camargo, M Constanza et al. (2018) Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 67:1239-1246
Singh, Kshipra; Coburn, Lori A; Asim, Mohammad et al. (2018) Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses. Cancer Res 78:4303-4315
Corley, Douglas A; Peek Jr, Richard M (2018) When Should Guidelines Change? A Clarion Call for Evidence Regarding the Benefits and Risks of Screening for Colorectal Cancer at Earlier Ages. Gastroenterology 155:947-949
Gobert, Alain P; Al-Greene, Nicole T; Singh, Kshipra et al. (2018) Distinct Immunomodulatory Effects of Spermine Oxidase in Colitis Induced by Epithelial Injury or Infection. Front Immunol 9:1242
Raghunathan, Krishnan; Foegeding, Nora J; Campbell, Anne M et al. (2018) Determinants of Raft Partitioning of the Helicobacter pylori Pore-Forming Toxin VacA. Infect Immun 86:
Scoville, Elizabeth A; Allaman, Margaret M; Brown, Caroline T et al. (2018) Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn's Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling. Metabolomics 14:
Sierra, Johanna C; Asim, Mohammad; Verriere, Thomas G et al. (2018) Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut 67:1247-1260
Blosse, Alice; Lehours, Philippe; Wilson, Keith T et al. (2018) Helicobacter: Inflammation, immunology, and vaccines. Helicobacter 23 Suppl 1:e12517
Coburn, Lori A; Singh, Kshipra; Asim, Mohammad et al. (2018) Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis. Oncogene :

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