Single-cell Profiling Uncovers a -Expressing Metaplastic Gastric Cell Type Sustained by -driven Inflammation.

UNLABELLED

Mechanisms for ()-driven stomach cancer are not fully understood. In a transgenic mouse model of gastric preneoplasia, concomitant infection and induction of constitutively active KRAS (+KRAS+) alters metaplasia phenotypes and elicits greater inflammation than either perturbation alone. Gastric single-cell RNA sequencing showed that +KRAS+ mice had a large population of metaplastic pit cells that expressed the intestinal mucin and the growth factor amphiregulin Flow cytometry and IHC-based immune profiling revealed that metaplastic pit cells were associated with macrophage and T-cell inflammation. Accordingly, expansion of metaplastic pit cells was prevented by gastric immunosuppression and reversed by antibiotic eradication of . Finally, MUC4 expression was significantly associated with proliferation in human gastric cancer samples. These studies identify an -associated metaplastic pit cell lineage, also found in human gastric cancer tissues, whose expansion is driven by -dependent inflammation.

SIGNIFICANCE

Using a mouse model, we have delineated metaplastic pit cells as a precancerous cell type whose expansion requires -driven inflammation. In humans, metaplastic pit cells show enhanced proliferation as well as enrichment in precancer and early cancer tissues, highlighting an early step in the gastric metaplasia to cancer cascade.