Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene.
Genomes of human cancer cells are characterized by numerous chromosomal aberrations of uncertain pathogenetic significance. Here, in an inducible mouse model of melanoma, we characterized metastatic variants with an acquired focal chromosomal amplification that corresponds to a much larger amplification in human metastatic melanomas. Further analyses identified Nedd9, an adaptor protein related to p130CAS, as the only gene within the minimal common region that exhibited amplification-associated overexpression. A series of functional, biochemical, and clinical studies established NEDD9 as a bona fide melanoma metastasis gene. NEDD9 enhanced invasion in vitro and metastasis in vivo of both normal and transformed melanocytes, functionally interacted with focal adhesion kinase and modulated focal contact formation, and exhibited frequent robust overexpression in human metastatic melanoma relative to primary melanoma. Thus, comparative oncogenomics has enabled the identification and facilitated the validation of a highly relevant cancer gene governing metastatic potential in human melanoma.
Kim
Minjung
M
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Gans
Joseph D
JD
Nogueira
Cristina
C
Wang
Audrey
A
Paik
Ji-Hye
JH
Feng
Bin
B
Brennan
Cameron
C
Hahn
William C
WC
Cordon-Cardo
Carlos
C
Wagner
Stephan N
SN
Flotte
Thomas J
TJ
Duncan
Lyn M
LM
Granter
Scott R
SR
Chin
Lynda
L
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000502:physiology; D005784:Gene Amplification; D015870:Gene Expression; D023281:Genomics; D006801:Humans; D066298:In Vitro Techniques; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology / Q000556:secondary*; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009857:Oncogenes; D010750:Phosphoproteins / Q000235:genetics*; D034622:RNA Interference; D013045:Species Specificity
D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse