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

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.