Cargando…
The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness
Neuroblastoma is an aggressive childhood cancer arising from sympatho-adrenergic neuronal progenitors. The low survival rates for high-risk disease point to an urgent need for novel targeted therapeutic approaches. Detailed molecular characterization of the neuroblastoma genomic landscape indicates...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959226/ https://www.ncbi.nlm.nih.gov/pubmed/31937834 http://dx.doi.org/10.1038/s41598-019-57076-5 |
_version_ | 1783487550137040896 |
---|---|
author | Mus, Liselot M. Lambertz, Irina Claeys, Shana Kumps, Candy Van Loocke, Wouter Van Neste, Christophe Umapathy, Ganesh Vaapil, Marica Bartenhagen, Christoph Laureys, Genevieve De Wever, Olivier Bexell, Daniel Fischer, Matthias Hallberg, Bengt Schulte, Johannes De Wilde, Bram Durinck, Kaat Denecker, Geertrui De Preter, Katleen Speleman, Frank |
author_facet | Mus, Liselot M. Lambertz, Irina Claeys, Shana Kumps, Candy Van Loocke, Wouter Van Neste, Christophe Umapathy, Ganesh Vaapil, Marica Bartenhagen, Christoph Laureys, Genevieve De Wever, Olivier Bexell, Daniel Fischer, Matthias Hallberg, Bengt Schulte, Johannes De Wilde, Bram Durinck, Kaat Denecker, Geertrui De Preter, Katleen Speleman, Frank |
author_sort | Mus, Liselot M. |
collection | PubMed |
description | Neuroblastoma is an aggressive childhood cancer arising from sympatho-adrenergic neuronal progenitors. The low survival rates for high-risk disease point to an urgent need for novel targeted therapeutic approaches. Detailed molecular characterization of the neuroblastoma genomic landscape indicates that ALK-activating mutations are present in 10% of primary tumours. Together with other mutations causing RAS/MAPK pathway activation, ALK mutations are also enriched in relapsed cases and ALK activation was shown to accelerate MYCN-driven tumour formation through hitherto unknown ALK-driven target genes. To gain further insight into how ALK contributes to neuroblastoma aggressiveness, we searched for known oncogenes in our previously reported ALK-driven gene signature. We identified ETV5, a bona fide oncogene in prostate cancer, as robustly upregulated in neuroblastoma cells harbouring ALK mutations, and show high ETV5 levels downstream of the RAS/MAPK axis. Increased ETV5 expression significantly impacted migration, invasion and colony formation in vitro, and ETV5 knockdown reduced proliferation in a murine xenograft model. We also established a gene signature associated with ETV5 knockdown that correlates with poor patient survival. Taken together, our data highlight ETV5 as an intrinsic component of oncogenic ALK-driven signalling through the MAPK axis and propose that ETV5 upregulation in neuroblastoma may contribute to tumour aggressiveness. |
format | Online Article Text |
id | pubmed-6959226 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69592262020-01-16 The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness Mus, Liselot M. Lambertz, Irina Claeys, Shana Kumps, Candy Van Loocke, Wouter Van Neste, Christophe Umapathy, Ganesh Vaapil, Marica Bartenhagen, Christoph Laureys, Genevieve De Wever, Olivier Bexell, Daniel Fischer, Matthias Hallberg, Bengt Schulte, Johannes De Wilde, Bram Durinck, Kaat Denecker, Geertrui De Preter, Katleen Speleman, Frank Sci Rep Article Neuroblastoma is an aggressive childhood cancer arising from sympatho-adrenergic neuronal progenitors. The low survival rates for high-risk disease point to an urgent need for novel targeted therapeutic approaches. Detailed molecular characterization of the neuroblastoma genomic landscape indicates that ALK-activating mutations are present in 10% of primary tumours. Together with other mutations causing RAS/MAPK pathway activation, ALK mutations are also enriched in relapsed cases and ALK activation was shown to accelerate MYCN-driven tumour formation through hitherto unknown ALK-driven target genes. To gain further insight into how ALK contributes to neuroblastoma aggressiveness, we searched for known oncogenes in our previously reported ALK-driven gene signature. We identified ETV5, a bona fide oncogene in prostate cancer, as robustly upregulated in neuroblastoma cells harbouring ALK mutations, and show high ETV5 levels downstream of the RAS/MAPK axis. Increased ETV5 expression significantly impacted migration, invasion and colony formation in vitro, and ETV5 knockdown reduced proliferation in a murine xenograft model. We also established a gene signature associated with ETV5 knockdown that correlates with poor patient survival. Taken together, our data highlight ETV5 as an intrinsic component of oncogenic ALK-driven signalling through the MAPK axis and propose that ETV5 upregulation in neuroblastoma may contribute to tumour aggressiveness. Nature Publishing Group UK 2020-01-14 /pmc/articles/PMC6959226/ /pubmed/31937834 http://dx.doi.org/10.1038/s41598-019-57076-5 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Mus, Liselot M. Lambertz, Irina Claeys, Shana Kumps, Candy Van Loocke, Wouter Van Neste, Christophe Umapathy, Ganesh Vaapil, Marica Bartenhagen, Christoph Laureys, Genevieve De Wever, Olivier Bexell, Daniel Fischer, Matthias Hallberg, Bengt Schulte, Johannes De Wilde, Bram Durinck, Kaat Denecker, Geertrui De Preter, Katleen Speleman, Frank The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness |
title | The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness |
title_full | The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness |
title_fullStr | The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness |
title_full_unstemmed | The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness |
title_short | The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness |
title_sort | ets transcription factor etv5 is a target of activated alk in neuroblastoma contributing to increased tumour aggressiveness |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959226/ https://www.ncbi.nlm.nih.gov/pubmed/31937834 http://dx.doi.org/10.1038/s41598-019-57076-5 |
work_keys_str_mv | AT musliselotm theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT lambertzirina theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT claeysshana theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT kumpscandy theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT vanloockewouter theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT vannestechristophe theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT umapathyganesh theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT vaapilmarica theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT bartenhagenchristoph theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT laureysgenevieve theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT deweverolivier theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT bexelldaniel theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT fischermatthias theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT hallbergbengt theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT schultejohannes theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT dewildebram theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT durinckkaat theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT deneckergeertrui theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT depreterkatleen theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT spelemanfrank theetstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT musliselotm etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT lambertzirina etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT claeysshana etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT kumpscandy etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT vanloockewouter etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT vannestechristophe etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT umapathyganesh etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT vaapilmarica etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT bartenhagenchristoph etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT laureysgenevieve etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT deweverolivier etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT bexelldaniel etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT fischermatthias etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT hallbergbengt etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT schultejohannes etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT dewildebram etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT durinckkaat etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT deneckergeertrui etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT depreterkatleen etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness AT spelemanfrank etstranscriptionfactoretv5isatargetofactivatedalkinneuroblastomacontributingtoincreasedtumouraggressiveness |