Identification of the Cell of Origin in Barrett's Esophagus

PROJECT SUMMARY (See instructions): Barrett's esophagus (BE) is a rapidly increasing preneoplastic disorder that arises in the setting of chronic inflammation and repeated injury from acid and bile reflux. While the histopathologic progression of BE to EAC has been well characterized, the cell of origin for BE has been poorly understood. Recent studies have focused on the possibility of transdifferentiation of squamous epitheilial progenitors, but work from our group has pointed to progenitors that reside in the gastric cardia. Using a newly created L2-IL-1beta transgenic mouse model of BE/EAC, in which IL-1 beta is over expressed in the esophageal squamous mucosa, we have observed an early upregulation of progenitors expressing Lgr5, Cck2r, and Dclkl in the proximal stomach just below the squamocolumnar junction (SCJ). These progenitors, which are absent in normal esophageal squamous mucosa, are amplified first in the gastric cardia by inflammation and bile acids, and migrate over time proximally into the SCJ in association with expansion of BE. These progenitors are also absent from normal human squamous esophageal epithelium but markedly upregulated in human Barrett's. Preliminary studies by our group using inducible Cre-ERT2 mice have shown that Lgr5 and Cck2r mark active stem or progenitor cells In the cardia, while Dclkl marks a long-lived quiescent stem cell in the gastric cardia. Based on these studies, we propose three specific aims: (1) What is the role of active (Lgr5+ or Cck2r+) stenri/progenitor cells present in the cardia in the development of Barrett's esophagus in the mouse? Lineage tracing studies of Lgr5+ and Cck2r+ progenitors will be performed in the normal gastic cardia, in the BE/EAC lesions in the L2-lL-1b mouse, and in the surgical reflux (esophagojejunostomy) model of BE. (2), What is the role of quiescent (Dclkl) stem cells present in the cardia in the development of BE in the mouse? Both constitutive and inducible lines of Dclkl-Cre mice will be used in lineage tracing studies, and the relationship to other progenitors explored, (3). Does administration of YF476 (a Cck2r-specific antagonist) to human patients with BE inhibit cellular proliferation? We will carry out a pilot clinical trial to determine if targeting cardia progenitors early on may represent a potential chemoprevention strategy.