CDX2 is an amplified lineage-survival oncogene in colorectal cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-11, Vol.109 (46), p.E3196-E3205
• Main Authors: Salari, Keyan, Spulak, Mary E, Cuff, Justin, Forster, Andrew D, Giacomini, Craig P, Huang, Stephanie, Ko, Melissa E, Lin, Albert Y, van de Rijn, Matt, Pollack, Jonathan R
• Format: Article
• Language: English
• Subjects: Animals; Binding sites; Biological Sciences; carcinogenesis; CDX2 Transcription Factor; Cell Line, Tumor; Cell Survival; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Chromosomes; Chromosomes, Human, Pair 13 - genetics; Chromosomes, Human, Pair 13 - metabolism; Colorectal cancer; colorectal neoplasms; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Models, Animal; Gene Amplification; Genetics; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Mice; Mutation; neoplasm cells; NIH 3T3 Cells; oncogenes; PNAS Plus; Signal transduction; Survival analysis; transcription (genetics); transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Wnt Signaling Pathway - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1206004109

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 multistep model of colorectal tumorigenesis.