Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia

Gastroenterology. 2009 Apr;136(4):1368-78. doi: 10.1053/j.gastro.2008.12.066. Epub 2009 Jan 9.


Background & aims: Invasive pancreatic ductal adenocarcinoma is thought to originate from duct-like lesions called pancreatic intraepithelial neoplasia (PanIN). PanINs progress from low grade (PanIN-1) to high grade (PanIN-3) as the cells attain molecular alterations to key regulatory genes, including activating mutations in the KRAS protooncogene. Despite a well-documented progression model, our knowledge of the initiator cells of PanINs and the transcriptional networks and signaling pathways that impact PanIN formation remains incomplete.

Methods: In this study, we examined the importance of the acinar-restricted transcription factor Mist1 to KrasG12D-induced mouse PanIN (mPanIN) formation in 3 different mouse models of pancreatic cancer.

Results: In the absence of Mist1 (Mist1KO), KrasG12D-expressing mice exhibited severe exocrine pancreatic defects that were rescued by ectopic expression of Mist1 in acinar cells. mPanIN development was greatly accelerated in Mist1KO/KrasG12D/+ pancreata, and in vitro assays revealed that Mist1KO acinar cells were predisposed to convert to a ductal phenotype and activate epidermal growth factor receptor (EGFR) and Notch-signaling pathways.

Conclusions: We propose that convergence of EGFR, Notch, and Kras pathways in acinar cells lacking Mist1 leads to enhanced mPanIN formation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carcinoma in Situ / metabolism*
  • Carcinoma in Situ / pathology
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Disease Progression
  • ErbB Receptors / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Receptors, Notch / metabolism
  • Signal Transduction / physiology


  • Basic Helix-Loop-Helix Transcription Factors
  • Bhlha15 protein, mouse
  • Receptors, Notch
  • ErbB Receptors
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)