Esophageal cancers rank sixth among all cancers in worldwide causes of death. Moreover, the five-year survival rate remains at a dismal 17%, largely due to the difficulty of early detection. To improve and develop preventative, early treatment and early detection strategies, there is a significant, immediate need for a better understanding of the origins and early stages of esophageal cancers. This project proposal aims to (1) identify the cellular and regional origins of esophageal squamous cell carcinoma (eSCC), one of the two major types of esophageal cancer and (2) identify the role of acid induced injury and inflammation in determining the locale and latency of eSCC. These aims will test the hypothesis that the squamocolumnar junction between the esophagus and stomach exhibits a uniquely heightened susceptibility to eSCC development due to an increased level of gastric acid exposure. Our aims will be accomplished through an innovative approach that will utilize a combination of chemical carcinogenesis and previously unpublished genetically engineered mouse models for eSCC. The overarching goal of this proposal is to define the cellular origins and cell extrinsic conditions that lead to eSCC formation through the development of a unique and impactful panel of mouse models. Furthermore, we will use this experimental system to evaluate the potential preventative effects of antacid treatment on eSCC initiation and progression. Taken together, the studies outlined in this proposal will enable future work that will exploit this new model platform for pre-clinical testing of preventative, early intervention and curative strategies.