Abstract 6071: Activation of NOTCH signaling via DLL1 is mediated by APE1-redox-dependent NF-κB activation in esophageal adenocarcinoma

Abstract Esophageal adenocarcinoma (EAC) is one of the most lethal of all human malignancies. EAC arises in the setting of Barrett’s esophagus, which is an intestinal metaplastic precursor lesion that develops from chronic reflux of gastrointestinal contents (especially acidic bile salts). Here we report that NOTCH signaling is activated in the esophagus through a unique pathway during exposure to acidic bile salts and progression to EAC. Using a combination of public databases, EAC cell line models, transgenic mice, and patient tissue samples, we detected significant upregulation of several NOTCH signaling components in EAC. Activated NOTCH signaling was confirmed by nuclear accumulation of NOTCH1 cleaved fragment (NICD) with corresponding up-regulation of NOTCH targets in EAC cells in response to acidic bile salts. Moreover, we identified DLL1 as the predominant ligand contributing NOTCH1 activation. Remarkably, DLL1 was regulated by direct cross talk between redox and inflammatory pathways that are activated during both reflux and malignant transformation. Mechanistically, the APE1 redox function transcriptionally up-regulated NF-κB in response to bile salts. This licensed NF-κB to transcriptionally up-regulate DLL1 to activate and stimulate downstream NOTCH1 signaling, thereby defining a novel APE1-NF-kB-NOTCH pro-tumorigenic pathway. This pathway was important for maintaining tumor initiating (cancer “stem cell-like”) properties in vitro, recurrently detected in genetically engineered mouse models of EAC and in EAC patient samples in vivo, and portended an overall poor prognosis. Collectively, these findings indicate that progression from chronic injury to malignancy in the esophagus is driven by a unique mechanism that links redox balance, inflammation, embryonic development (NOTCH) together into a common pro-tumorigenic pathway that is intrinsic to EAC cells. Citation Format: Lei Chen, Heng Lu, Dunfa Peng, Longlong Cao, Zheng Chen, Ajaz Bhat, Alexander Zaika, Shutian Zhang, Wael El-Rifai. Activation of NOTCH signaling via DLL1 is mediated by APE1-redox-dependent NF-κB activation in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6071.