Esophageal adenocarcinoma (EAC) is a highly fatal cancer with 5-year survival under 20%. Alarmingly, the incidence of cancer of the esophagus has increased significantly over the past 30 years. EAC arises from a known precursor lesion, termed Barrett's esophagus (BE), that can be easily recognized at endoscopy. However, current clinical strategies of screening and surveillance are inadequate and EAC diagnosis often occurs at advanced and unresectable stages of the disease. Veterans are increased risk for BE and EAC compared to the general population due to increased risk factors (including age >50 and male gender). There is an urgent clinical need to improve strategies for the detection, prognostication, and treatment of BE and EAC. This translational research proposal aims to elucidate the molecular carcinogenesis of EAC, with the ultimate goal of reducing the burden associated with this deadly cancer. We used integrative computational and genetic analyses to identify common mechanisms that underlie EAC tumor progression. We identified that the TGF? pathway is highly active in EAC compared to non-malignant BE. The TGF?/Smad pathway has tumor suppressive properties in epithelial cells, including inhibition of cell proliferation and induction of apoptosis, and the functional TGF? pathway elements are frequently lost through mutation in gastrointestinal malignancies. However, in established cancers TGF? signaling can promote invasion and metastasis, suggesting opposing roles for TGF? signaling that depend on disease stage. In contrast, our preliminary findings show that the TGF? pathway fails to inhibit the growth of pre-malignant dysplastic BE cells in addition to EAC cells; on the contrary TGF? induces growth of EAC cells even in the presence of functional TGF? pathway components. Further, the pro-tumorigenic TGF? pathway effects are evident in EAC that are either wild-type or mutant for Smad4, a canonical mediator of TGF? signaling. Together, our preliminary studies indemnify an alternative model for the oncogenic TGF? with early hyperactivation of an unconventional, Smad4 independent, Smad2/3 dependent pathway. Our findings have important translational implications. In Aim 1, we will investigate the molecular determinants of the oncogenic TGF? signaling in EAC carcinogensis. In Aim 2, we will assess impact of disrupting oncogenic TGF? signaling in highly relevant pre-clinical models of EAC. Of particular importance, LY2157299 (galunisertib), an orally bioavailable small molecule inhibitor of the TGF? Receptor ? Type 1, is currently being tested in Phase II trials in other malignancies and represents a new therapeutic strategy that can be rapidly evaluated for this lethal cancer. This study is highly innovative and will improve our ability to both prevent and treat cancer of the esophagus. The scientific proposal and career development activities described here will serve an essential role in my development as a clinical gastroenterologist at the VA and as a scientist with research program aimed at improving early detection and treatment of gastrointestinal cancer. Through this CDA-2 award, I will receive additional training and experience related to cancer biology, systems biology, and pre-clinical models of human cancer that will be essential to reach my goal. Also, in this rich mentored environment, I will develop skills required to perform independent research.