Esophageal squamous cell cancer is a deadly malignancy with alcohol a major risk factor. The overarching aim of this R21 proposal is to understand the role of human esophageal myofibroblasts (HEMFs) in the development of esophageal squamous cell carcinoma. We hypothesize that HEMFs exposed to alcohol provide a permissive environment for development of ESCC. We plan to test our hypothesis using a combination of 2D and 3D culture models in the following specific aims (1). Determine the effect of alcohol and its metabolite acetaldehyde on HEMF proliferation/apoptosis, gene and secretory profile, and function in the presence and absence of acidic bile salts. (2). Define effects of alcohol treated HEMFs in the presence/absence of acidic bile salts on overlying epithelial proliferation, differentiation, dysplasia and epithelial-mesenchymal transition and interrogate involved signaling pathways. (3). Determine HEMF location, proliferation, and genomic alterations in squamous intraepithelial dysplasia and ESCC and determine the effect on the epithelium. Understanding the effect of alcohol on HEMFs and HEMF-epithelial interactions prior to dysplasia or invasive cancer will identify the molecular basis by which alcohol increases risk for esophageal cancer and lead to novel approaches that therapeutically target a permissive tumor microenvironment.
Esophageal squamous cell carcinoma is one of the deadliest cancers in the world with alcohol a major risk factor. Little is known about the effect of alcohol on the esophageal stroma. The proposed research will fundamentally advance our understanding of the mechanisms by which alcohol use leads to esophageal cancer.