TY - JOUR
T1 - CDX2 is an amplified lineage-survival oncogene in colorectal cancer
AU - Salari, Keyan
AU - Spulak, Mary E.
AU - Cuff, Justin
AU - Forster, Andrew D.
AU - Giacomini, Craig P.
AU - Huang, Stephanie
AU - Ko, Melissa E.
AU - Lin, Albert Y.
AU - De Rijn, Mattvan
AU - Pollack, Jonathan R.
PY - 2012/11/13
Y1 - 2012/11/13
N2 - 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.
AB - 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.
KW - 13q amplification
KW - CDK8
KW - Integrative genomics
KW - Lineage dependency
KW - Lineage-addiction oncogene
UR - http://www.scopus.com/inward/record.url?scp=84869224866&partnerID=8YFLogxK
U2 - 10.1073/pnas.1206004109
DO - 10.1073/pnas.1206004109
M3 - Article
C2 - 23112155
AN - SCOPUS:84869224866
SN - 0027-8424
VL - 109
SP - E3196-E3205
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -