title: A modular and flexible ESC-based mouse model of pancreatic cancer.
abstract: Genetically engineered mouse models (GEMMs) have greatly expanded our knowledge of pancreatic ductal adenocarcinoma (PDAC) and serve as a critical tool to identify and evaluate new treatment strategies. However, the cost and time required to generate conventional pancreatic cancer GEMMs limits their use for investigating novel genetic interactions in tumor development and maintenance. To address this problem, we developed flexible embryonic stem cell (ESC)-based GEMMs that facilitate the rapid generation of genetically defined multiallelic chimeric mice without further strain intercrossing. The ESCs harbor a latent Kras mutant (a nearly ubiquitous feature of pancreatic cancer), a homing cassette, and other genetic elements needed for rapid insertion and conditional expression of tetracycline-controlled transgenes, including fluorescence-coupled shRNAs capable of efficiently silencing gene function by RNAi. This system produces a disease that recapitulates the progression of pancreatic cancer in human patients and enables the study and visualization of the impact of gene perturbation at any stage of pancreas cancer progression. We describe the use of this approach to dissect temporal roles for the tumor suppressor Pten and the oncogene c-Myc in pancreatic cancer development and maintenance.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
authors.forename: Michael
authors.initials: M
authors.lastname: Saborowski
authors.forename: Anna
authors.initials: A
authors.lastname: Saborowski
authors.forename: John P
authors.initials: JP
authors.lastname: Morris
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bosbach
authors.forename: Lukas E
authors.initials: LE
authors.lastname: Dow
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells; D055785:Gene Knockdown Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D016271:Proto-Oncogene Proteins c-myc; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: RMCE; embryonic stem cell; kras; mouse model; pancreas; pancreatic cancer