Barrett's esophagus is an increasingly prevalent, preneoplastic disorder that results primarily from gastroduodenal reflux of acid and bile. The applicant group, which includes established investigators from Columbia University, the University of Pennsylvania, and the Mayo Clinic, propose a multidisciplinary, multicenter, translational research program to study the origins and pathogenesis of the disorder. The team, many of whom have collaborated in the past, will focus on the role of chronic inflammation and bile acids in the upregulation of established and novel stem cell markers, and possible ways to target these progenitor cells. The proposal builds on extensive basic science findings, the development of novel transgenic (L2-IL-1beta) and surgical models of BE/esophageal adenocarcinoma, and preliminary analyses of human BE tissues. The groups will bring to the network a very large BE patient population, experienced Barrett's clinical investigators, and bench researchers with extensive experience with stem cells and inflammatory models of Gl cancer. Three projects are proposed. Project 1 will focus on the role of Notch signaling in models of Barrett's esophagus, and will determine the effects of Notch inhibition or Notch activation on progression to dysplasia. Project 2 will seek to characterize the cell of origin in Barrett's esophagus in our mouse models. We will use constituitive and inducible mouse models of Cre expression to lineage trace active and quiescent progenitors that are upregulated in our model and in human BE. Additionally, we will carry out a pilot clinical trial using an antagonist of a G-protein coupled receptor expressed on progenitor cells upregulated in BE. Finally, Project 3 will aim to identify novel biomarkers and gene signatures in BE, correlating data sets from animal and human models, clarifying the importance of non-goblet cell columnar epithelium and changes in the gastric cardia. We will also assemble a cohort of patients undergoing radiofrequency ablation, identifying biomarkers of response to therapy and using successfully ablated patients as a novel human model to study the development of BE. Overall, these studies aim to elucidate the earliest stages and cell types that contribute to BE pathogenesis in order to better stratify risk and develop preventive therapies.

Public Health Relevance

The goal of the present proposal is to generate a dear understanding of the mechanisms underlying the development of Barrett's esophagus and EAC, and subsequently to transform this knowledge into clinical practice that will improve patient outcomes and decrease the disease burden of EAC. Our novel preclinical models serve as the foundation for testing these hypotheses, which are then brought ultimately to the clinical arena in a true translational. bench-to bedside approach through biomarker and chemoprevention studies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1)
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Yassin, Rihab R,
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Kasagi, Yuta; Chandramouleeswaran, Prasanna M; Whelan, Kelly A et al. (2018) The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive Epithelial Changes. Cell Mol Gastroenterol Hepatol 5:333-352
May, Michael; Abrams, Julian A (2018) Emerging Insights into the Esophageal Microbiome. Curr Treat Options Gastroenterol 16:72-85
Huo, Xiaofang; Zhang, Xi; Yu, Chunhua et al. (2018) Aspirin prevents NF-?B activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus. Gut 67:606-615
Chan, Daniel K; Zakko, Liam; Visrodia, Kavel H et al. (2017) Breath Testing for Barrett's Esophagus Using Exhaled Volatile Organic Compound Profiling With an Electronic Nose Device. Gastroenterology 152:24-26
Ma, M; Shroff, S; Feldman, M et al. (2017) Risk of malignant progression in Barrett's esophagus indefinite for dysplasia. Dis Esophagus 30:1-5
Kraft, Crystal L; Rappaport, Jeffrey A; Snook, Adam E et al. (2017) GUCY2C maintains intestinal LGR5+ stem cells by opposing ER stress. Oncotarget 8:102923-102933
Zakko, Liam; Lutzke, Lori; Wang, Kenneth K (2017) Screening and Preventive Strategies in Esophagogastric Cancer. Surg Oncol Clin N Am 26:163-178
Hayakawa, Yoku; Fox, James G; Wang, Timothy C (2017) The Origins of Gastric Cancer From Gastric Stem Cells: Lessons From Mouse Models. Cell Mol Gastroenterol Hepatol 3:331-338
Zakko, Liam; Visrodia, Kavel; Wang, Kenneth K et al. (2017) Editorial: The Effect of Bias on Estimation of Improved Survival After Diagnosis of Barrett's Esophagus. Am J Gastroenterol 112:1265-1266
Lee, Yoomi; Urbanska, Aleksandra M; Hayakawa, Yoku et al. (2017) Gastrin stimulates a cholecystokinin-2-receptor-expressing cardia progenitor cell and promotes progression of Barrett's-like esophagus. Oncotarget 8:203-214

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