Promoterless transposon mutagenesis drives solid cancers via tumor suppressor inactivation

Aziz Aiderus, Ana M. Contreras-Sandoval, Amanda L. Meshey, Justin Y. Newberg, Jerrold M. Ward, Deborah A. Swing, Neal G. Copeland, Nancy A. Jenkins, Karen M. Mann, Michael B. Mann

Research output: Contribution to journalArticle

Abstract

A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty transposon mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.

Original languageEnglish (US)
Article number225
Pages (from-to)1-24
Number of pages24
JournalCancers
Volume13
Issue number2
DOIs
StatePublished - Jan 2 2021

Keywords

  • Cancer hallmarks
  • Cul3
  • E3 ubiquitin ligase
  • Ras signaling
  • Rasa1
  • Sleeping Beauty transposon mutagenesis
  • Trip12
  • Tumor suppressor driver genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Promoterless transposon mutagenesis drives solid cancers via tumor suppressor inactivation'. Together they form a unique fingerprint.

Cite this