Understanding eosinophilic esophagitis-mediated inhibition of esophageal cancer

Project Summary With a 5-year survival rate of <20% and substantial lack of response to the current standard of care, esophageal squamous cell carcinoma (ESCC) is among the deadliest malignancies worldwide. Notably, patients with the food-allergen-mediated inflammatory disease eosinophilic esophagitis (EoE) fail to develop esophageal cancer according to recent epidemiological studies. Our own publication recently used mouse models of EoE and ESCC to demonstrated that EoE limits carcinogenesis in vivo. Based on our own published and preliminary data, we hypothesize that EoE activates anti-tumor responses in the esophagus to limit ESCC carcinogenesis. We will test this hypothesis by: Determining the functional role of senescence in EoE-mediated suppression of ESCC (Aim 1); determining the impact of IL-13 on esophageal epithelial cell fate (Aim 2); and defining the direct impact of EoE upon the cellular landscape of ESCC esophageal mucosa and associated inflammatory cells (Aim 3). These studies provide the first investigation of the direct mechanisms through which EoE can suppress esophageal carcinogenesis. Ultimately, we aim to leverage these mechanisms to develop novel approaches for prevention and therapy of ESCC. As allergic inflammation has been reported to be negatively associated with various types of cancer, our findings may have significant implications in the field of cancer biology field. The work outlined in this application will further provide the PI with a comprehensive scientific research experience encompassing discovery and subsequent target validation in the field of cancer biology. The research component of the proposal coupled with the detailed training plan will support the PI as she pursues her goal of becoming an independent investigator at a top academic research institution.