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

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 an...

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Autores principales: Mathieu, Véronique, Pirker, Christine, Schmidt, Wolfgang M., Spiegl-Kreinecker, Sabine, Lötsch, Daniela, Heffeter, Petra, Hegedus, Balazs, Grusch, Michael, Kiss, Robert, Berger, Walter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380575/
https://www.ncbi.nlm.nih.gov/pubmed/22535842
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author Mathieu, Véronique
Pirker, Christine
Schmidt, Wolfgang M.
Spiegl-Kreinecker, Sabine
Lötsch, Daniela
Heffeter, Petra
Hegedus, Balazs
Grusch, Michael
Kiss, Robert
Berger, Walter
author_facet Mathieu, Véronique
Pirker, Christine
Schmidt, Wolfgang M.
Spiegl-Kreinecker, Sabine
Lötsch, Daniela
Heffeter, Petra
Hegedus, Balazs
Grusch, Michael
Kiss, Robert
Berger, Walter
author_sort Mathieu, Véronique
collection PubMed
description 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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spelling pubmed-33805752012-06-27 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 Hegedus, Balazs Grusch, Michael Kiss, Robert Berger, Walter Oncotarget Research Papers 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. Impact Journals LLC 2012-04-24 /pmc/articles/PMC3380575/ /pubmed/22535842 Text en Copyright: © 2012 Mathieu et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
spellingShingle Research Papers
Mathieu, Véronique
Pirker, Christine
Schmidt, Wolfgang M.
Spiegl-Kreinecker, Sabine
Lötsch, Daniela
Heffeter, Petra
Hegedus, Balazs
Grusch, Michael
Kiss, Robert
Berger, Walter
Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation
title Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation
title_full Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation
title_fullStr Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation
title_full_unstemmed Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation
title_short Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation
title_sort aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380575/
https://www.ncbi.nlm.nih.gov/pubmed/22535842
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