Project 3 will be directed towards the origins of BE and response to ablative therapy, and represents an extension of the hypotheses from Projects 1 and 2, specifically that chronic inflammation and activation of stem/progenitor cells are key factors in the development of BE. Data from histopathologic studies in humans and from our L2-IL-1 beta mouse model suggest that CLE (independent of goblet cells) may represent tissue at risk for neoplastic progression. However, there are currently no validated biomarkers of CLE as tissue with neoplastic potential. In patients who progress, endoscopic therapy with radiofrequency ablation (RFA) can eradicate both dysplasia and intestinal metaplasia. We have found that 25-35% of ablated patients develop IM and even dysplasia at the GE junction. We therefore propose to study this patient population as a novel human model for the development of BE through evaluation of biomarkers for recurrent IM. Using this same cohort, we will evaluate pre-treatment markers that predict short- and long-term response to RFA, as the ability to identify non-responders prior to treatment would allow better targeting of resources to those who would predictably respond to the therapy. In order to address these issues, we propose three aims: 1) To determine the site of origin of BE based on gene expression profiles in humans. We will extend the findings from the L2-IL-1beta mouse model to humans by comparing gene expression profiles of Barrett's and cardia tissue in BE patients and controls. We will evaluate specific markers of stem cell activation as well as new biologically-based markers identified by genomic analyses, as potential new biomarkers for CLE and BE;2) To determine whether stem cell markers predict recurrence of BE after ablation therapy. We hypothesize that the recurrence of IM after ablative therapy is secondary to stem cell differentiation into an intestinal phenotype in the cardia, and that central obesity may impact this process;3) To determine biomarkers which can predict response to ablation therapy in patients with BE. We will prospectively follow a large cohort of BE patients with HGD/EAC who undergo RFA. We will determine if pi6 status impacts efficacy will explore the possibility that epigenetic changes represent potentially modifiable predictors of non-response to therapy.

Public Health Relevance

This Project is designed to identify biologically-based and clinically-useful biomarkers of tissue at risk for neoplastic progression as well as of response to ablation therapy. These results will result in improved risk stratification in BE and better targeting of resources for patients who are candidates for ablative therapy, while simultaneously providing key information regarding the origins of Barrett's esophagus.

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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Columbia University (N.Y.)
New York
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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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