Epithelial-stromal cross-talk in esophageal inflammation and carcinogenesis.

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 DESCRIPTION (provided by applicant): Esophageal adenocarcinoma (EAC) is the fastest growing malignancy in the West and the 6th most lethal cancer in the world. Gastro-esophageal reflux disease (GERD) is a chronic-inflammatory disorder associated with an 8 fold increased risk of EAC. Exposure to gastric acid, duodenal bile, and luminal pathogens leads to inflammation and ulceration, exposing stromal cells to noxious signals and ongoing injury. An aberrant epithelial response to injury and inflammation ultimately culminates in EAC. Disruptions in epithelial-stromal interactions likely further contribute to inflammation and malignancy. GERD therapy primarily relies on acid suppression therapy which has not changed cancer risk. Investigation of intercellular cross-talk in GERD is therefore critical to elucidating early biologcal drivers of malignancy. This grant application addresses this knowledge deficit by the novel use of human esophageal myofibroblasts adapted into a 3D organotypic model that recapitulates esophageal stratified squamous epithelium. Myofibroblasts are stromal cells that regulate epithelial homeostasis, inflammation and proliferation via paracrine mechanisms. Preliminary work suggests that in response to GERD stimuli human esophageal myofibroblasts (MFs) are potent sources of pro- carcinogenic cytokines and members of the bone morphogenetic protein (BMP) family. The overarching hypothesis of this project is that human esophageal myofibroblasts (MFs) regulate epithelial inflammation and repair in GERD via paracrine mediated signaling pathways that when disrupted lead to esophageal malignancy. To address this hypothesis, we will use biochemical and genetic approaches in the 3D organotypic model to mimic human esophageal MF exposure to luminal and epithelial derived noxious signals to delineate the epithelial-stromal cross talk that governs inflammatory and proliferative responses in GERD. We will determine the mechanism by which human esophageal MF cytokine secretion in GERD activates signaling pathways that regulate epithelial inflammation and epithelial growth. This aim is significant because it will delineate biologically relevant cytokine driven stromal-epithelial interactions and sheds insight into the mechanism linking inflammation and carcinogenesis. We will also determine the mechanism by which human esophageal secretion of BMPs regulates epithelial proliferation, differentiation and apoptosis in GERD. This aim is significant because it delineates novel BMP driven stromal-epithelial interactions in the GERD and provides the rationale for therapeutic targeting of potentially modifiable signaling pathways.