Tff2 marks gastric corpus progenitors that give rise to pyloric metaplasia/SPEM following injury

Background Spasmolytic polypeptide-expressing metaplasia (SPEM) arises in the gastric corpus in response to oxyntic atrophy, but its cellular origin and role in gastric cancer remain unclear. Objective To define the cellular origin of SPEM in the gastric corpus and its relationship to gastric dysplasia and cancer progression. Design Tff2-CreERT2 knock-in mice were used for lineage tracing and genetic ablation to characterise Tff2 + corpus progenitor cells. Acute injury, chief cell ablation, H. pylori infection and Kras G12D activation models were applied. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed on human gastric tissues to validate differentiation trajectories. Results Highly proliferative Tff2 + progenitors were localised to the corpus isthmus and generated multiple secretory lineages including chief cells, but lacked long-term self-renewal. Following acute injury or chief cell loss, Tff2 + progenitors rapidly expanded to form transient SPEM. Genetic ablation of Tff2 + progenitors abolished SPEM formation, whereas ablation of Lgr5-DTR- or Gif-rtTA–labelled chief cells enhanced SPEM derived from Tff2 + progenitors. on H. pylori infection or Kras G12D activation, Tff2 + progenitors progressed to SPEM and dysplasia. Kras activation in Tff2 + progenitors promoted direct progression to dysplasia through acquisition of stem cell–like properties. In contrast, Kras-mutant SPEM and chief cells failed to progress to dysplasia. Human scRNA-seq and spatial transcriptomics revealed distinct differentiation trajectories from isthmus proliferating cells to SPEM or gastric cancer. Conclusions Tff2 + corpus progenitors represent a common cellular origin for SPEM and gastric dysplasia, challenge the conventional stepwise model of gastric carcinogenesis and indicate divergent differentiation programmes from Tff2 + progenitors.