title: Mist1-KrasG12D knock-in mice develop mixed differentiation metastatic exocrine pancreatic carcinoma and hepatocellular carcinoma.
abstract: 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 KrasG12D 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.
authors.affiliation: Department of Medicine, Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania, USA. tuvesond@mail.med.upenn.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Liqin
authors.initials: L
authors.lastname: Zhu
authors.forename: Aarthi
authors.initials: A
authors.lastname: Gopinathan
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Willis
authors.forename: Leili
authors.initials: L
authors.lastname: Kachatrian
authors.forename: Rebecca
authors.initials: R
authors.lastname: Grochow
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Pin
authors.forename: Natalia Y
authors.initials: NY
authors.lastname: Mitin
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Taparowsky
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C491312:Bhlha15 protein, mouse