The effects of TWEAK-FN14 Signaling Axis in Esophageal Adenocarcinoma

Esophageal adenocarcinoma is one of the largest growing cancer types in the United States and the whole world. One of the only known precursors to EAC is Barrett’s Esophagus, the changing of the normal squamous cells which line the esophagus into intestinal cells, following repeated exposure to gastric acids via gastroesophageal reflux disease. There is limited knowledge of the mutations and drivers that contribute to EAC’s low 5-year survival rates, demonstrating a need to identify new therapeutic targets. Given the development of EAC from chronic inflammation and acidic microenvironment, elevated expression of tumor necrosis factor receptor super family member 12A (TNFRSF12A, FN14) and its corresponding ligand, TWEAK, is correlated with disease progression. The functional role of the TWEAK/FN14 signaling axis is well documented in other cancer types, contributing to tumor invasion, migration, and survival. However, reports have shown the TWEAK/FN14 signaling axis can contribute “pro-cancer” and “anti-cancer” phenotypes in different tumor microenvironments. In this study, we seek to demonstrate the functional role of TWEAK and FN14 in EAC survival and migration. We hypothesized TWEAK/FN14 signaling would promoted EAC cell survival and migration. In this study, we illustrate increased expression of FN14 with disease progression. Following treatment with TWEAK, human EAC cell lines had increased sensitivity to standard chemotherapy treatment in vitro. Treatment with TWEAK also correlated with increased cellular migration, most likely in correlation with NF-κB activation. Finally, we showed that inhibition of FN14 via siRNA significantly reduced EAC survival and increased efficacy of standard of care treatments. This data suggests a diverse functional role of the TWEAK/FN14 signaling axis in EAC, and may be a potential target for novel therapeutics.