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

Abstract In Brief Tu et al. show that Tff2 + corpus isthmus cells are TA progenitors, and they, not chief cells, are the primary source of SPEM following injury. Upon Kras mutation, these progenitors directly progress to dysplasia, bypassing metaplasia, highlighting them as a potential origin of gastric cancer. Highlights Tff2 + corpus cells are TA progenitors that give rise to secretory cells. Tff2 + progenitors, not chief cells, are the primary source of SPEM after injury. Kras-mutant Tff2 + progenitors progress directly to dysplasia, bypassing metaplasia. Multi-omics analysis reveals distinct trajectories for SPEM and gastric cancer. Abstract Figure Graphical abstract Pyloric metaplasia, also known as spasmolytic polypeptide-expressing metaplasia (SPEM), arises in the corpus in response to oxyntic atrophy, but its origin and role in gastric cancer remain poorly understood. Using Tff2-CreERT knockin mice, we identified highly proliferative Tff2 + progenitors in the corpus isthmus that give rise to multiple secretory lineages, including chief cells. While lacking long-term self-renewal ability, Tff2 + corpus progenitors rapidly expand to form short-term SPEM following acute injury or loss of chief cells. Genetic ablation of Tff2 + progenitors abrogated SPEM formation, while genetic ablation of GIF + chief cells enhanced SPEM formation from Tff2 + progenitors. In response to H. pylori infection, Tff2 + progenitors progressed first to metaplasia and then later to dysplasia. Interestingly, induction of Kras G12D mutations in Tff2 + progenitors facilitated direct progression to dysplasia in part through the acquisition of stem cell-like properties. In contrast, Kras-mutated SPEM and chief cells were not able to progress to dysplasia. Tff2 mRNA was downregulated in isthmus cells during progression to dysplasia. Single-cell RNA sequencing and spatial transcriptomics of human tissues revealed distinct differentiation trajectories for SPEM and gastric cancer. These findings challenge the conventional interpretation of the stepwise progression through metaplasia and instead identify Tff2 + progenitor cells as potential cells of origin for SPEM and possibly for gastric cancer.