Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation
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1 Laboratory of Toxicology, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium
2 Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria
3 Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
4 Neuromuscular Research Department, Center for Anatomy and Cell Biology, Medical University Vienna, Vienna, Austria
5 Department of Neurosurgery, Landesnervenklinik Wagner-Jauregg Hospital, Linz, Austria
6 Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria
7 2nd Institute of Pathology, Semmelweis University, Budapest, Hungary
* Denotes equal contribution
Received: March 30, 2012; Accepted: April 20, 2012; Published: April 24, 2012;
Keywords: malignant melanoma, aneuploidy, local aggressiveness, xenograft, integrative genomics
Walter Berger, email:
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.
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