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.
Competing Interests: Declaration of interests P.L. is Sr. Director of Single-Cell Systems Pharmacology at DarwinHealth, Inc., & Company that has licensed some of the algorithms used in this manuscript from Columbia University. A.C. is a founder, equity holder, and consultant of DarwinHealth Inc., a company that has licensed some of the algorithms used in this work from Columbia University. Columbia University is also an equity holder in DarwinHealth Inc.
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