Clonal cell states link Barrett’s esophagus and esophageal adenocarcinoma

Abstract

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. To address this, we performed single-cell lineage tracing and transcriptional profiling of patient cells isolated from metaplastic and healthy tissue. Our analysis revealed discrete lineages in Barrett's esophagus, normal esophagus, and gastric cardia. Transitional basal progenitor cells of the gastroesophageal junction were unexpectedly related to both esophagus and gastric cardia cells. Barrett's esophagus was polyclonal, with lineages that contained all progenitor and differentiated cell types. In contrast, precancerous dysplastic foci 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 full disease trajectory, from its origin to cancer.

Promises and Limitations of Current Models for Understanding Barrett’s Esophagus and Esophageal Adenocarcinoma

“…Beyond gene expression, single-cell approaches can identify clonal mutations by selectively amplifying mitochondrial cDNA. 11 Using these novel techniques, progenitor cells at the GEJ were associated with clones of both normal squamous mucosa and gastric cardia. In BE, multiple distinct clones were present within a BE segment, a concept well-described in a recent review.…”

“… 12 Clonal mitochondrial analysis suggested that some EACs develop from the transformation of a single BE clone associated with abnormal Wnt signaling, although the authors hypothesized that other carcinogenic pathways were also possible. 11 …”

Non-genetic differences underlie variability in proliferation among esophageal epithelial clones

“…To determine if the proliferative signatures established in the EPC2-hTERT cell line model was reflected in healthy human esophageal tissue, we collated and analyzed multiple published scRNA-seq datasets of healthy human esophageal epithelium 9,[42][43][44] . After stringent quality control filtering, we combined data from 62,216 cells across 26 patients and batch-corrected the data (Fig.…”

“…The count matrices for EPC2-hTERT were generated as mentioned above. scRNA-seq datasets of healthy human esophageal epithelium 9,[42][43][44] and patients with ESCC 44,45 were previously published. Each dataset was individually filtered based on standard filtering before combining them using Seurat V4 62 .…”