The Role of the Microenvironment in Barrett's Esophagus

PROJECT SUMMARY Barrett’s esophagus is an increasingly prevalent, preneoplastic disorder resulting from acid/bile reflux and chronic inflammation at the GE junction. The BETRNet Research Center 1 represents a translational research program from Columbia University, the University of Pennsylvania and the Mayo Clinic. The team, which has been highly productive, has been focused on the role of microbiota and the tumor microenvironment in the development and progression of Barrett’s esophagus and esophageal adenocarcinoma. The group also includes additional collaborative sites at MIT, the Dana Farber Cancer Institute and Munich Technical University, and utilizes heavily a Microbiome and Metabolomics Core at Penn-CHOP. Thus, the team comprises broad and unique expertise in mouse models, genomics, microbiology and clinical research. Our research program is built around the hypothesis that the inflammation-dependent tumor microenvironment, modulated by the GE junction microbiome, is critical for early progression of esophageal carcinogenesis. The proposal utilizes both the novel transgenic (L2-ILB) and innovative 3D organoid models, along with a cross-sectional study of 150 Barrett’s and non-Barrett’s patients. Project 1 studied the role of microbiota and myeloid cells in the L2-ILB mouse model of Barrett’s esophagus. This project incorporated germ-free housing, antibiotic eradication, colonization with defined flora, myeloid cell ablation and correlative human studies. Project 2 focused on the characterization of microenvironment drivers in BE, and included FACS/IHC analysis of CAFs and immune cells (MDSCs/Tregs) in BE patients, along with 3D organoids in culture, as well as defining the role of IL-6 in response to epithelial TP53 mutations and immune cell activation. Finally, Project 3 seeks to identify novel biomarkers and gene signatures related to the microbiome and microenvironment. The study analyzed bile acids, a product of microbes, and minimally invasive tests such as saliva/breath test/tethered capsule sponge to analyze microbes to develop screening/surveillance strategies. Overall, these projects will advance the science of the microbiome and microenvironment in BE that will hopefully lead to translational applications. For the extension period, we propose to continue and complete experiments and analyses related to the three Projects.