A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma

Vincent W. Keng, Augusto Villanueva, Derek Y. Chiang, Adam J. Dupuy, Barbara J. Ryan, Ilze Matise, Kevin A.T. Silverstein, Aaron Sarver, Timothy K. Starr, Keiko Akagi, Lino Tessarollo, Lara S. Collier, Scott Powers, Scott W. Lowe, Nancy A. Jenkins, Neal G. Copeland, Josep M. Llovet, David A. Largaespada

Research output: Contribution to journalArticlepeer-review

158 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)264-274
Number of pages11
JournalNature biotechnology
Volume27
Issue number3
DOIs
StatePublished - Mar 2009

Bibliographical note

Funding Information:
The authors wish to thank Christine E. Nelson, Stefanie S. Breitbarth, Michelle K. Gleason and Geoff Hart for their excellent technical support; Jason B. Bell for performing the hydrodynamic injections; and Heidi Gruelich, Dana Farber Cancer Institute, for her kind gift pBabe-Puro-LTR-EGFR. We are also grateful to the Minnesota Supercomputing Institute for providing extensive computational resources (hardware and systems administration support) used to carry out the sequence analysis. A.V. is supported by a Sheila Sherlock fellowship from the European Association for the Study of the Liver. L.S.C. is supported by a 1K01CA122183-01 grant from the National Cancer Institute. N.G.C., N.A.J. and L.T. are supported by the Department of Health and Human Services, National Institutes of Health and the National Cancer Institute. J.M.L. is supported by the US National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK076986-01), Spanish National Institute of Health (SAF-2007-61898) and Samuel Waxman Cancer Research Foundation. D.A.L. is supported by U01 CA84221 and R01 CA113636 grants from the National Cancer Institute.

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