A modular and flexible ESC-based mouse model of pancreatic cancer
- Michael Saborowski1,
- Anna Saborowski1,
- John P. Morris IV1,
- Benedikt Bosbach1,
- Lukas E. Dow1,
- Jerry Pelletier2,
- David S. Klimstra1 and
- Scott W. Lowe1,3,4
- 1Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
- 2McGill University, Montreal, Quebec H3A OG4, Canada;
- 3Howard Hughes Medical Institute, New York, New York 10032, USA
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.
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Footnotes
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↵4 Corresponding author
E-mail lowes{at}mskcc.org
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.232082.113.
Freely available online through the Genes & Development Open Access option.
- Received October 10, 2013.
- Accepted December 4, 2013.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.