Clonal cell states link gastroesophageal junction tissues, metaplasia, and cancer [MAESTER]

Barrett's esophagus is a common type of metaplasia and a precursor of esophageal adenocarcinoma. However, the cell states and lineage connections underlying the origin, maintenance, and progression of Barrett's esophagus have not been resolved in humans. Here, we performed single-cell lineage tracing and transcriptional profiling of patient cells isolated from metaplastic and healthy tissue. Our analysis unexpectedly revealed that the squamous esophagus and gastric cardia contained cells belonging to common lineages that also included transitional basal progenitor cells; both esophageal and gastric tissues were also related to Barrett's esophagus. Barrett's esophagus biopsies consisted of multiple clones, with lineages that contained all progenitor and differentiated cell types. In contrast, precancerous dysplastic lesions were initiated by the expansion of a single molecularly aberrant Barrett's esophagus clone. Together, these findings provide a comprehensive view of the cell dynamics of Barrett's esophagus, linking cell states along the disease trajectory, from its origin to cancer. Overall design: Performed single-cell lineage tracing and transcriptional profiling of patient cells isolated from metaplastic and healthy tissue.