CDX2 is an amplified lineage-survival oncogene in colorectal cancer

Keyan Salari, Mary E. Spulak, Justin Cuff, Andrew D. Forster, Craig P. Giacomini, Stephanie Huang, Melissa E. Ko, Albert Y. Lin, Mattvan De Rijn, Jonathan R. Pollack*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

The mutational activation of oncogenes drives cancer development and progression. Classic oncogenes, such as MYC and RAS, are active across many different cancer types. In contrast, "lineage-survival" oncogenes represent a distinct and emerging class typically comprising transcriptional regulators of a specific cell lineage that, when deregulated, support the proliferation and survival of cancers derived from that lineage. Here, in a large collection of colorectal cancer cell lines and tumors, we identify recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor 2 (CDX2), a regulator of normal intestinal lineage development and differentiation, as a target of the amplification. In contrast to its described role as a colorectal tumor suppressor, CDX2 when amplified is required for the proliferation and survival of colorectal cancer cells. Further, transcriptional profiling, binding-site analysis, and functional studies link CDX2 to Wnt/β-catenin signaling, itself a key oncogenic pathway in colorectal cancer. These data characterize CDX2 as a lineage-survival oncogene deregulated in colorectal cancer. Our findings challenge a prevailing view that CDX2 is a tumor suppressor in colorectal cancer and uncover an additional piece in the multistepmodel of colorectal tumorigenesis.

Original languageEnglish
Pages (from-to)E3196-E3205
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number46
DOIs
StatePublished - 13 Nov 2012
Externally publishedYes

Keywords

  • 13q amplification
  • CDK8
  • Integrative genomics
  • Lineage dependency
  • Lineage-addiction oncogene

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