ABSTRACT
Esophageal adenocarcinoma (EAC), a highly aggressive cancer with limited therapeutic options, often arises in the backdrop of a molecularly-complex esophageal metaplasia disorder, Barrett’s Esophagus (BE). Using transcriptomics and systems biology analyses of treatment-naïve malignant/pre-malignant biopsy tissues, we found Eph receptor B2 (EphB2) tyrosine kinase signaling to be frequently hyperactivated during early stages of EAC development, and across the BE-EAC continuum. Functional studies revealed EphB2 to be an upstream post-translational regulator of c-MYC activity and as a key molecular dependency in BE/EAC. Single-cell transcriptomics in a porcine esophageal 3D spheroid model showed enhanced EphB2 and MYC activity to be significantly associated with BE-like cell fate. shRNA-based knockdown of EphB2 or small molecule inhibitors of MEK, that modulate MYC protein stability, proved effective in suppressing EAC tumor growth in vivo. These findings point to EphB2-MYC axis as an early promoter of EAC and a novel therapeutic vulnerability in this increasingly-prevalent esophageal malignancy.
STATEMENT OF SIGNIFICANCE We identify EphB2 signaling as a potential master regulator and early promoter of esophageal adenocarcinoma, and the proto-oncogene MYC as a key downstream effector of EphB2 function. Targeting the EphB2-MYC axis could be a promising therapeutic strategy for these often refractory and lethal EAC tumors.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Grant Support: This research was supported by PHS awards: R01 CA204549 (K. Guda), U01 CA152756 (K. Guda), Case BETRNet U54 CA163060 (J.E. Willis, A. Chak, K. Guda), Case GI SPORE P50 CA150964 (J.E. Willis, A. Chak, K. Guda, A. E. Blum), K08 DK098528 (K.S. Garman), R01 DK118022 (K.S. Garman), 3T32-DK007568-28S2 (O. Martinez-Uribe), K25 DK115904 (V. Varadan), P30 CA043703 (V. Varadan, K. Guda); CDA-2 1IK2CX001831 United States (U.S.) Department of Veterans Affairs, Biomedical Laboratory Research and Development Service (A. E. Blum); and the DeGregorio Family Foundation, the Savone Family, and the Esophageal Cancer Awareness Association (K. Guda).
Disclosures: The authors have no potential conflicts of interest to disclose.