Notch Signaling Drives Stemness and Tumorigenicity of Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) ranks sixth in cancer mortality in the world and its incidence has risen dramatically in the western population over the last decades. Data presented herein strongly suggest that Notch signaling is critical for EAC and underlies resistance to chemotherapy. We present evidence that Notch signaling drives a cancer stem cell phenotype by regulating genes that establish stemness. Using patient derived xenograft models we demonstrate that inhibition of Notch by gamma-secretase inhibitors (GSI) is efficacious in downsizing tumor growth. Moreover, we demonstrate that Notch activity in a patient’s EUS-derived biopsy might predict outcome to chemotherapy. Therefore, this study provides a proof of concept that inhibition of Notch activity will have efficacy in treating EAC, offering a rationale to lay the foundation for a clinical trial to evaluate the efficacy of GSI in EAC treatment.