Gastric cancer is the third leading cause of cancer-associated death worldwide. The global cancer statistics report indicated an estimated 1,033,701 new gastric cancer cases and 782,685 deaths occurred in 2018. Several studies have reported frequent association of gastric adenocarcinoma with Helicobacter pylori (H. pylori) infection. The World Health Organization has classified H. pylori as a class I carcinogen and the main risk factor for gastric cancer. Despite efforts to eradicate H. pylori, infection remains a global health problem with almost half of the world’s population infected. According to a recent study of U.S soldiers deployed to the Middle East and Far East, the incidence of H. pylori infection was 7.3 percent per year compared to 2.5 percent of U.S. military recruits living at home. This increase represents a major increase in risk. When epithelial cells lose their protective capacity, they become prone to the carcinogenic effects of H. pylori, leading to the development of intestinal metaplasia, gastric dysplasia and progression to cancer. Our recent preliminary data in this proposal, demonstrates frequent overexpression of oncogenic FGFR4 signaling in gastric cancer. Using in vitro and in vivo models as well as H. pylori infection, we demonstrated a novel link between pro-inflammatory signaling (STAT3) and overexpression and activation of FGFR4. Functionally, we found that FGFR4 plays a critical role in regulating the level and activity of NRF2, a major anti-oxidant transcription factor, in response to cellular stress induced by H. pylori or chemotherapy. The FGFR4-NRF2 signaling promoted cell survival and resistance to chemotherapeutics. Based on our novel findings, we hypothesize that the dynamic pro-inflammatory oncogenic cross-talk between STAT3, FGFR4 and cellular anti- oxidant capacity plays a critical role in gastric tumorigenesis. Our goal is to understand the molecular and functional consequences of FGFR4 in the multi-step gastric carcinogenesis cascade. In this proposal, we will investigate mechanisms of activation of FGFR4 in gastric tumorigenesis (Aim 1). We will determine the downstream molecular and biological functions of activation of FGFR4 and antioxidant response in gastric tumorigenesis in Aim 2. The translational significance of activation FGFR4 and NRF2 across stages of human gastric tumorigenesis will be investigated (Aim 3). In addition, Aim 3 will also determine the therapeutic significance of inhibiting FGFR4 as a single agent or in combinations with standards of care in pre-clinical models of gastric tumorigenesis. This proposal tackles etiology-based biologically-relevant questions to uncover novel information regarding the role of H. pylori, inflammation, oxidative stress, and tumorigenic signaling in the multi-step gastric tumorigenesis. A successful completion of this project will have a positive impact on understanding the biology and identification of diagnostic, prognostic and possibly therapeutic...