title: Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.
abstract: Melanoma is a devastating skin cancer characterized by distinct biological subtypes. Besides frequent mutations in growth- and survival-promoting genes like BRAF and NRAS, melanomas additionally harbor complex non-random genomic alterations. Using an integrative approach, we have analysed genomic and gene expression changes in human melanoma cell lines (N=32) derived from primary tumors and various metastatic sites and investigated the relation to local growth aggressiveness as xenografts in immuno-compromised mice (N=22). Although the vast majority >90% of melanoma models harbored mutations in either BRAF or NRAS, significant differences in subcutaneous growth aggressiveness became obvious. Unsupervised clustering revealed that genomic alterations rather than gene expression data reflected this aggressive phenotype, while no association with histology, stage or metastatic site of the original melanoma was found. Genomic clustering allowed separation of melanoma models into two subgroups with differing local growth aggressiveness in vivo. Regarding genes expressed at significantly altered levels between these subgroups, a surprising correlation with the respective gene doses (>85% accordance) was found. Genes deregulated at the DNA and mRNA level included well-known cancer genes partly already linked to melanoma (RAS genes, PTEN, AURKA, MAPK inhibitors Sprouty/Spred), but also novel candidates like SIPA1 (a Rap1GAP). Pathway mining further supported deregulation of Rap1 signaling in the aggressive subgroup e.g. by additional repression of two Rap1GEFs. Accordingly, siRNA-mediated down-regulation of SIPA1 exerted significant effects on clonogenicity, adherence and migration in aggressive melanoma models. Together our data suggest that an aneuploidy-driven gene expression deregulation drives local aggressiveness in human melanoma.
authors.affiliation: Laboratory of Toxicology, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Mathieu
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Schmidt
authors.forename: Sabine
authors.initials: S
authors.lastname: Spiegl-Kreinecker
authors.forename: Daniela
authors.initials: D
authors.lastname: Lötsch
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Balazs
authors.initials: B
authors.lastname: Hegedus
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
mesh_terms: D000782:Aneuploidy; D000818:Animals; D045744:Cell Line, Tumor; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D018628:Gene Dosage / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C490403:SIPA1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf