Single-cell profiling uncovers aMuc4-expressing metaplastic gastric cell type sustained byHelicobacter pylori-specific inflammation

Abstract

AbstractMechanisms forHelicobacter pylori(Hp)-driven stomach cancer are not fully understood. In a transgenic mouse model of gastric preneoplasia, concomitantHpinfection and induction of constitutively active KRAS (Hp+KRAS+) alters metaplasia phenotypes and elicits greater inflammation than either perturbation alone. Gastric single-cell RNA-seq showed thatHp+KRAS+ mice had a large population of metaplastic pit cells that expressed the intestinal mucinMuc4and the growth factor amphiregulin. Metaplastic pit cells were associated with macrophage and T cell inflammation and prevented by gastric immunosuppression. Lineage tracing showed thatMuc4was not dependent on cell-intrinsic KRAS activity, and lineage-derived cells had a limited propensity for growth as organoids, demonstrating that metaplastic pit cells are largely not self- renewing. Finally, MUC4 expression was significantly associated with proliferation in human gastric cancer samples. These studies identify anHp-associated metaplastic pit cell lineage, also found in human gastric cancer tissues, whose expansion is driven byHp-dependent inflammation.Statement of SignificanceUsing a mouse model, we have delineated metaplastic pit cells as a pre-cancerous cell type whose expansion requiresH. pylori-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.