Bile Acids Initiate Lineage‐Addicted Gastroesophageal Tumorigenesis by Suppressing the EGF Receptor‐AKT Axis

Abstract While bile acids are a risk factor for tumorigenesis induced by reflux disease, the mechanisms by which they contribute to neoplasia remain undefined. Here, we reveal that in gastroesophageal junction (GEJ) cells bile acids activate a tissue‐specific developmental program defining the intestinal epithelial cell phenotype characterizing GEJ metaplasia. Deoxycholic acid (DCA) inhibited phosphorylation of EGF receptors (EGFRs) suppressing the proto‐oncogene AKT. Suppression of EGFRs and AKT by DCA actuated an intestine‐specific cascade in which NF‐κB transactivated the tissue‐specifi c transcription factor CDX2. In turn, CDX2 orchestrated a lineage‐specific differentiation program encompassing genes characterizing intestinal epithelial cells. Conversely, progression from metaplasia to invasive carcinoma in patients, universally associated with autonomous activation of EGFRs and/or AKT, was coupled with loss of this intestinal program. Thus, bile acids induce intestinal metaplasia at the GEJ by activating the lineage‐specifi c differentiation program involving suppression of EGFR and AKT, activating the NF‐κB‐CDX2 axis. Induction of this axis provides the context for lineage‐addicted tumorigenesis, in which autonomous activation of AKT corrupts adaptive intestinal NF‐κB signaling, amplifying tumorigenic programs.