Eosinophilic esophagitis-associated epithelial remodeling may limit esophageal carcinogenesis

Abstract

AbstractUnder homeostatic conditions, esophageal epithelium displays a proliferation/differentiation gradient that is generated as proliferative basal cells give rise to suprabasal cells then terminally differentiated superficial cells. This proliferation/differentiation gradient is perturbed in esophageal pathologies both benign and malignant. Esophageal cancer is among the deadliest forms of human malignancy with 5-year survival rates of <20%. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two most common subtypes of esophageal cancer. Gastroesophageal reflux disease (GERD) is a primary risk factor for EAC. Although GERD and the food allergy-mediated condition eosinophilic esophagitis (EoE) are both associated with chronic esophageal inflammation and epithelial remodeling, including basal cell hyperplasia, epidemiological evidence suggests that EoE patients do not develop esophageal malignancy. Here, we perform single cell RNA-sequencing in murine models of EoE and ESCC to delineate the effects that these two conditions have specifically upon the cellular landscape of esophageal epithelium. In mice with EoE or ESCC, we find expansion of cell populations as compared to normal esophageal epithelium. In mice with EoE, we detect expansion of 4 suprabasal populations coupled with depletion of 4 basal cell populations. By contrast, mice with ESCC display expansion of 4 basal populations as well as depletion of 3 superficial populations. We further evaluated modules of co-expressed genes in EoE- and ESCC-enriched epithelial cell clusters. Senescence, glucocorticoid receptor signaling, and granulocyte-macrophage colony-stimulating factor pathways were associated with EoE-enriched clusters while pathways associated with cell proliferation and metabolism were identified in ESCC-enriched clusters. Finally, by pairing murine models of EoE and ESCC, we demonstrate that exposure to EoE inflammation limits esophageal carcinogenesis. Our findings provide the first functional investigation of the relationship between EoE and esophageal cancer and suggest that esophageal epithelial remodeling events occurring in response to EoE inflammation may limit act to esophageal carcinogenesis which may have future implications for leveraging allergic inflammation-associated alterations in epithelial biology to prevent and/or treat esophageal cancer.