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

Wee-Keong Vincent 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: Journal article publicationJournal articleAcademic researchpeer-review

154 Citations (Scopus)

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
Pages (from-to)264-274
Number of pages11
JournalNature Biotechnology
Volume27
Issue number3
DOIs
Publication statusPublished - 1 Mar 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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