Interaction of Helicobacter pylori with Gastric Progenitor Cells

• Applicant: Professor Dr. Michael Sigal
• Subject Area: Gastroenterology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 245745606

Gastric cancer is the fifth highest cancer type diagnosed in Europe. It is evident that the most important risk factor for the development of gastric cancer is infection with the gram-negative bacterium Helicobacter pylori (H. pylori). Because progenitor cells play a major role in carcinogenesis, I hypothesize that a direct or indirect interaction of the bacteria with these cells may be the critical point for deregulation of cell turnover and dedifferentiation leading to cancer. The idea of stem cell involvement in pathogenesis of cancer is based on the hypothesis that the tissue progenitor cells assemble enough molecular lesions to evade homeostatic control which results in deregulated proliferation and cancer. Of note, relatively little information is available about the effects of H. pylori infection on stem cells. Our preliminary data indicate that H. pylori interact with proliferating cells in gastric glands, which are located in the stem cell niche. This interplay possibly disrupts the differentiation of progenitor or stem cells by introducing molecular damage and results in malignant transformation. In this project, I propose to find out, which stem cell populations are activated by H. pylori induced tissue damage in vivo. I will also characterize H pylori’s direct effects on proliferation and differentiation of the gastric epithelium using a novel 3D gastric organoid system. Transgenic mouse models will be used to identify the stem cells being activated by the bacterium. We will perform lineage tracing experiments for established gastric stem cell markers Lgr-5 and villin in H. pylori infected mice. Moreover we will use a novel 3D gastric organoid culture system to investigate the direct interaction of bacteria with specific subpopulations of gastric epithelial cells and characterize the cellular effects of this interaction. We will study the alterations in proliferation and differentiation caused by H. pylori infection. Bacteria lacking major virulence factor CagA are available and will be used to understand its relevance in stem cell activation. Transcriptional and protein analysis will reveal, which changes are caused by the infection in particular stem cell populations and will give new insights into the pathophysiology of gastric cancer and may provide new therapeutic targets for patients with H. pylori caused disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Manuel R Amieva, Ph.D.