Mutational and functional analysis reveals ADAMTS18 metalloproteinase as a novel driver in melanoma.
The disintegrin-metalloproteinases with thrombospondin domains (ADAMTS) genes have been suggested to function as tumor suppressors as several have been found to be epigenetically silenced in various cancers. We performed a mutational analysis of the ADAMTS gene family in human melanoma and identified a large fraction of melanomas to harbor somatic mutations. To evaluate the functional consequences of the most commonly mutated gene, ADAMTS18, six of its mutations were biologically examined. ADAMTS18 mutations had little effect on melanoma cell growth under standard conditions, but reduced cell dependence on growth factors. ADAMTS18 mutations also reduced adhesion to laminin and increased migration in vitro and metastasis in vivo. Melanoma cells expressing mutant ADAMTS18 had reduced cell migration after short hairpin RNA-mediated knockdown of ADAMTS18, suggesting that ADAMTS18 mutations promote growth, migration, and metastasis in melanoma.
National Human Genome Research Institute, Room 5140, Building 50, 50 South Drive, MSC 8000, Bethesda, MD 20892-8000, USA.
Xiaomu
X
Wei
Todd D
TD
Prickett
Cristina G
CG
Viloria
Alfredo
A
Molinolo
Jimmy C
JC
Lin
Isabel
I
Cardenas-Navia
Pedro
P
Cruz
Steven A
SA
Rosenberg
Michael A
MA
Davies
Jeffrey E
JE
Gershenwald
Carlos
C
López-Otín
Yardena
Y
Samuels
D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism*; D000071096:ADAMTS Proteins; D002448:Cell Adhesion / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004252:DNA Mutational Analysis; D052138:Genes, Neoplasm; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D045726:Metalloproteases / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009362:Neoplasm Metastasis
D045726:Metalloproteases; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C510099:ADAMTS18 protein, human