Transcription factors in ADM: PTF1A and MIST1

Pancreatic ADM is driven by the loss of acinar-lineage-specific transcription factors, such as pancreas transcription factor 1 subunit α (PTF1A), and the induction of the paired mesoderm homeobox protein 1 (PRRX1)–SOX9 axis^101–104. The molecular basis of ADM involves transforming growth factor-α (TGFα) and epidermal growth factor receptor (EGFR) signalling⁴³. Transgenic mice with Tgfa overexpression in the exocrine pancreas show evidence of duct-like cells⁴⁹. Acinar-specific expression of activated KRAS in mice (LSL-Kras^G12D/+;Ptf1a^Cre/+ mice) results in ADM¹⁰⁵. These metaplastic structures are proliferative and express Notch target genes^106–108. Transgenic expression of pancreatic and duodenal homeobox 1 (Pdx1) in the Ptf1a locus¹⁰⁹ results in the transition of acinar cells to duct-like cells and is regulated through signal transducer and activator of transcription 3 (STAT3) activation¹¹⁰. Pancreatic ADM lesions are associated with inflammation with a concomitant increase in MEK–ERK signalling¹¹¹. In human pancreatic sections, the close juxtaposition of ADM and PanIN suggests but does not prove progression of ADM to PanIN¹¹².

MIST1 is a global regulator of secretory cell architecture in multiple professional secretory cells, such as the acinar cells of the pancreas and salivary gland and the chief cells of the stomach¹¹³. During metaplasia in the stomach, salivary gland and pancreas, Mist1 is one of the first genes whose expression is decreased as cells scale down their secretion¹¹⁴, and forced expression or loss of MIST1 interferes with the induction of and recovery from metaplasia, respectively^115–117. Specifically, deletion of Mist1 leads to reduced levels of amylase, an enzyme specifically produced by mature exocrine pancreatic cells. Lineage tracing with cells expressing lacZ in the Mist1 locus (Mist1⁻lacZ⁺ cells) has demonstrated that these cells express ductal genes (for example, keratin 20 (Krt20)), suggesting that a cell-fate switch occurs in differentiated exocrine cells¹⁰². Of note is that the same Mist1⁻lacZ⁺ cells also maintain moderate levels of nuclear protein transcription regulator 1 (Nupr1)¹¹⁸ and regenerating islet-derived 1 (Reg1)¹¹⁹, genes that are expressed in embryonic pancreatic cells.

Deletion of Mist1 also blocks the differentiation of chief cells in the base of gastric glandular units¹²⁰. Consequently, uncommitted epithelial cells accumulate along the pathway where the derivatives of isthmus progenitor cells migrate¹²⁰. More importantly, SPEM occurs in the glandular stomach of Mist1^−/− mice upon treatment with the protonophore DMP-777 or its analogue L635, which induces the loss of parietal cells and inflammation¹²¹. These findings suggest that MIST1 is critical for the maturation of epithelial progenitor cells in the developing pancreas and glandular stomach. In both organs, blocking the differentiation process seems to facilitate the incidence of metaplasia. It will be interesting to determine whether conditional deletion of Mist1 in the adult also interferes with epithelial differentiation and facilitates metaplasia.