The incidence of esophageal adenocarcinoma (EAC) is rising rapidly in the U.S. Barrett's esophagus (BE) is the most widely accepted precursor lesion for EAC, but a major limitation to the study of EAC in the past has been absence of highly tractable in vitro or animal models of BE. In addition, BE has for many years been defined in the U.S. by the presence of goblet cells. In the intestine, goblet cell differentiation is known to occur in the setting of repressed Notch signaling. Notch signaling also plays a role in stem cell renewal as well as lineage commitment. However, while EAC is associated with classical intestinal metaplasia (IM) with goblet cell features, it is now clear that EAC often arises in the setting of non-1 M columnar lined esophagus (CLE). In the absence of goblet cells, CLE tissue is characterized by high levels of Notch signaling and progresses to high-grade dysplasia and EAC, Inhibition of Notch results in differentiation toward IM as well as inhibition of proliferation. Thus;recent findings in our animal models and by others have called into question the notion that goblet cell differentiation is strictly associated with cancer risk, and instead raise the interesting hypothesis that goblet cell differentiation and lower levels of Notch signaling in the setting of CLE may be associated with a reduced risk of progression to dysplasia. There have been several recent advances in this area by our group, including the development of a novel transgenic mouse model of BE/EAC, advances in surgical rodent models of reflux, and development of 3D-organotypic esophageal models, all of which can be used to address novel questions such as the role of Notch in BE/EAC. We will systematically evaluate this hypothesis, pursued at all three centers, by exploring the following inter-related Specific Aims: (1) Does blockade of Notch signaling and intestinal differentiation inhibit progression to dysplasia in a novel murine model of BE and EAC? (2) Does over activation of the Notch pathway accelerate progression to dysplasia in mouse models of Barrett's? (3) What is the role of Notch inhibition in 3D organotypic models of esophageal epithelium? (4) Is there a correlation between Notch expression and goblet cell numbers in BE, and do these represent potential markers for risk of progression to EAC?
Insights gained from this study address important questions regarding BE pathogenesis and progression to EAC. This project will further develop and validate these murine and organotypic models of BE and EAC, and to examine the relevance of our findings in patients with BE. This will greatly improve our ability to study, prevent, and treat BE and will foster development of novel therapeutic and preventive strategies.
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