Data from Mutational and Functional Analysis Reveals <i>ADAMTS18</i> Metalloproteinase as a Novel Driver in Melanoma

Abstract

<div>Abstract<p>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 <i>ADAMTS</i> 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, <i>ADAMTS18</i>, 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 <i>in vitro</i> and metastasis <i>in vivo</i>. Melanoma cells expressing mutant <i>ADAMTS18</i> had reduced cell migration after short hairpin RNA–mediated knockdown of ADAMTS18, suggesting that <i>ADAMTS18</i> mutations promote growth, migration, and metastasis in melanoma. Mol Cancer Res; 8(11); 1513–25. ©2010 AACR.</p></div>