More importantly, we have found that epithelial cells with aberrantly elevated EFNB1-EPHB4 interaction mainly originated from the basal layer of the epithelium and then expand to the up-layer when the disease progresses, which accelerates proliferation of diseased cells and triggers EMT, facilitating ESCC development and progression. Here, EFNB1 is linked to esophageal squamous cell carcinoma.