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

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 1; pp. 242 - 247
• Main Authors: Tuveson, David A, Zhu, Liqin, Gopinathan, Aarthi, Willis, Nicholas A, Kachatrian, Leili, Grochow, Rebecca, Pin, Christopher L, Mitin, Natalia Y, Taparowsky, Elizabeth J, Gimotty, Phyllis A, Hruban, Ralph H, Jacks, Tyler, Konieczny, Stephen F
• Format: Journal Article
• Language: English
• Published: 01.01.2006
• ISSN: 0008-5472

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 super(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 super(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 super(KrasG12D/+) cells in both pancreatic and hepatic neoplasia. Concomitant Trp53 super(+/-) mutation cooperated with Mist1 super(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)