title: CDX2 is an amplified lineage-survival oncogene in colorectal cancer.
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 multistep model of colorectal tumorigenesis.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Keyan
authors.initials: K
authors.lastname: Salari
authors.forename: Mary E
authors.initials: ME
authors.lastname: Spulak
authors.forename: Justin
authors.initials: J
authors.lastname: Cuff
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Forster
authors.forename: Craig P
authors.initials: CP
authors.lastname: Giacomini
authors.forename: Stephanie
authors.initials: S
authors.lastname: Huang
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Ko
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Lin
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005784:Gene Amplification; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins