Tff2 defines transit-amplifying pancreatic acinar progenitors that lack regenerative potential and are protective against Kras-driven carcinogenesis.

While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreER T2 -targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2 + cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic Kras G12D -targeted Tff2 + cells are resistant to PDAC initiation. However, Kras G12D activation in Tff2 + cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2 + cells prior to Kras G12D activation in Mist1 + acinar or Dclk1 + FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis.