Dedifferentiation unlocks keratinocyte competence for metaplasia and tumorigenesis in the foregut

Abstract

How tissue injury shapes cell competence to undergo malignant transformation remains poorly understood. Esophageal metaplasia, a precancerous lesion driven by chronic acid reflux, can arise from the conversion of squamous progenitors into a columnar-like state, but the factors governing this plasticity remain unclear. Here we show that GATA4, overexpressed in esophageal metaplasia and adenocarcinoma, drives columnar metaplasia in squamous progenitors at the squamo-columnar junction but is insufficient, and even toxic, in keratinocytes outside this region. Using inducible transgenic mouse models, we find that reactivation of Hedgehog signaling expands the pool of progenitors permissive to GATA4-mediated reprogramming, driving gastric-like metaplasia even within the esophagus. Combined Hedgehog activation and GATA4 expression further induce adenosquamous-like neoplasms and stromal and immune remodeling reminiscent of the metaplastic microenvironment. Since Hedgehog signaling is reactivated by gastroesophageal reflux, chronic injury may generate a field of dedifferentiated progenitors poised for malignant progression upon oncogene acquisition. These findings demonstrate that a prior cell state transition, induced by environmental injury, can unlock oncogenic competence, establishing a mechanistic framework linking epithelial plasticity, developmental transcription factor reactivation, and lineage-specific cancer susceptibility with broad implications for precancerous metaplastic states.