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Mist1-Kras^G12D Knock-In Mice Develop Mixed Differentiation Metastatic Exocrine Pancreatic Carcinoma and Hepatocellular Carcinoma

Departments of ¹ Medicine and ² Cancer Biology, Abramson Family Cancer Research Institute; ³ Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; ⁴ Department of Biological Sciences and the Purdue Cancer Center, Purdue University, West Lafayette, Indiana; ⁵ Massachusetts Institute of Technology Cancer Center and Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts; and ⁶ Departments of Pathology and Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: David A. Tuveson, Department of Medicine, University of Pennsylvania, 512 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160. Phone: 215-746-5560; Fax: 215-573-2486; E-mail: tuvesond{at}mail.med.upenn.edu or Stephen F. Konieczny, Department of Biological Sciences and the Purdue Cancer Center, Purdue University, Hansen Life Sciences Research Building, West Lafayette, IN 47907-2064. Phone: 765-494-7976; Fax: 765-496-2536; E-mail: sfk{at}bilbo.bio.purdue.edu.

Despite the prevalence of oncogenic Kras mutations in the earliest stages of pancreatic ductal adenocarcinoma, the cellular compartment in which oncogenic Kras initiates tumorigenesis remains unknown. To address this, we have gene targeted Kras^G12D into the open reading frame of Mist1, a basic helix-loop-helix transcription factor that is expressed during pancreatic development and required for proper pancreatic acinar organization. Although the pancreata of Mist1^KrasG12D/+ mutant mice predictably exhibited acinar metaplasia and dysplasia, the frequent death of these mice from invasive and metastatic pancreatic cancer with mixed histologic characteristics, including acinar, cystic, and ductal features, was unexpected and in contrast to previously described mutant mice that ectopically expressed the Kras oncogene in either acinar or ductal compartments. Interestingly, many of the mutant mice developed hepatocellular carcinoma, implicating Mist1^KrasG12D/+ cells in both pancreatic and hepatic neoplasia. Concomitant Trp53^+/– mutation cooperated with Mist1^KrasG12D/+ to accelerate lethality and was associated with advanced histopathologic findings, including parenchymal liver metastasis. These findings suggest that Mist1-expressing cells represent a permissive compartment for transformation by oncogenic Kras in pancreatic tumorigenesis. (Cancer Res 2006; 66(1): 242-7)