Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation

Véronique Mathieu, Christine Pirker, Wolfgang M. Schmidt, Sabine Spiegl-Kreinecker, Daniela Lötsch, Petra Heffeter, B. Hegedűs, Michael Grusch, Robert Kiss, Walter Berger

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)399-413
Number of pages15
JournalOncotarget
Volume3
Issue number4
Publication statusPublished - Apr 2012

Fingerprint

Aneuploidy
Heterografts
Melanoma
Gene Expression
Genes
Growth
Cluster Analysis
Aurora Kinase A
Mutation
Neoplasm Genes
Skin Neoplasms
Small Interfering RNA
Histology
Down-Regulation
Phenotype
Cell Line
Messenger RNA
Survival
DNA

Keywords

  • Aneuploidy
  • Integrative genomics
  • Local aggressiveness
  • Malignant melanoma
  • Xenograft

ASJC Scopus subject areas

  • Oncology

Cite this

Mathieu, V., Pirker, C., Schmidt, W. M., Spiegl-Kreinecker, S., Lötsch, D., Heffeter, P., ... Berger, W. (2012). Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation. Oncotarget, 3(4), 399-413.

Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation. / Mathieu, Véronique; Pirker, Christine; Schmidt, Wolfgang M.; Spiegl-Kreinecker, Sabine; Lötsch, Daniela; Heffeter, Petra; Hegedűs, B.; Grusch, Michael; Kiss, Robert; Berger, Walter.

In: Oncotarget, Vol. 3, No. 4, 04.2012, p. 399-413.

Research output: Contribution to journalArticle

Mathieu, V, Pirker, C, Schmidt, WM, Spiegl-Kreinecker, S, Lötsch, D, Heffeter, P, Hegedűs, B, Grusch, M, Kiss, R & Berger, W 2012, 'Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation', Oncotarget, vol. 3, no. 4, pp. 399-413.
Mathieu V, Pirker C, Schmidt WM, Spiegl-Kreinecker S, Lötsch D, Heffeter P et al. Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation. Oncotarget. 2012 Apr;3(4):399-413.
Mathieu, Véronique ; Pirker, Christine ; Schmidt, Wolfgang M. ; Spiegl-Kreinecker, Sabine ; Lötsch, Daniela ; Heffeter, Petra ; Hegedűs, B. ; Grusch, Michael ; Kiss, Robert ; Berger, Walter. / Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation. In: Oncotarget. 2012 ; Vol. 3, No. 4. pp. 399-413.
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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.",
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