Loss of the Acinar-Restricted Transcription Factor Mist1 Accelerates Kras-Induced Pancreatic Intraepithelial Neoplasia

Guanglu Shi, Liqin Zhu, Yan Sun, Ryan Bettencourt, Barbara Damsz, Ralph H. Hruban, Stephen F. Konieczny

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1368-1378
Number of pages11
JournalGastroenterology
Volume136
Issue number4
DOIs
StatePublished - Apr 2009

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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