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2009: Shi Guanglu; Zhu Liqin; Sun Yan; Bettencourt Ryan; Damsz Barbara; Hruban Ralph H; Konieczny Stephen F
Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia.
Gastroenterology 2009;136(4):1368-78.
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.

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