Research abstract
Article abstract
Nature Biotechnology 27, 264 - 274 (2009)
Published online: 22 February 2009 | doi:10.1038/nbt.1526
A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma
Vincent W Keng1,2, Augusto Villanueva3, Derek Y Chiang4,5, Adam J Dupuy6, Barbara J Ryan1,2, Ilze Matise1, Kevin A T Silverstein1,7, Aaron Sarver1,7, Timothy K Starr1,2, Keiko Akagi8, Lino Tessarollo8, Lara S Collier9, Scott Powers10, Scott W Lowe10, Nancy A Jenkins11, Neal G Copeland11, Josep M Llovet3,12,13 & David A Largaespada1,2
Abstract
We describe a system that permits conditional mobilization of a Sleeping Beauty (SB) transposase allele by Cre recombinase to induce cancer specifically in a tissue of interest. To demonstrate its potential for developing tissue-specific models of cancer in mice, we limit SB transposition to the liver by placing Cre expression under the control of an albumin enhancer/promoter sequence and screen for hepatocellular carcinoma (HCC)–associated genes. From 8,060 nonredundant insertions cloned from 68 tumor nodules and comparative analysis with data from human HCC samples, we identify 19 loci strongly implicated in causing HCC. These encode genes, such as EGFR and MET, previously associated with HCC and others, such as UBE2H, that are potential new targets for treating this neoplasm. Our system, which could be modified to drive transposon-based insertional mutagenesis wherever tissue-specific Cre expression is possible, promises to enhance understanding of cancer genomes and identify new targets for therapeutic development.
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
- Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
- BCLC Group-Liver Unit, HCC Translational Research Laboratory, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona 08036, Spain.
- Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
- Cancer Program, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
- Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242, USA.
- Biostatistics and Informatics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
- National Cancer Institute, Frederick, Maryland 21702, USA.
- Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, USA.
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
- Institute of Molecular and Cellular Biology, Singapore 138673, Singapore.
- Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, New York 10029, USA.
- Institució Catalana de Recerca i Estudis Avançats, Barcelona 08010, Spain.
Correspondence to: David A Largaespada1,2 e-mail: larga002@umn.edu
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