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The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness

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Abstract
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.
Keywords
UP-REGULATION, RNA-SEQ, EXPRESSION, MYCN, DIFFERENTIATION, NEURONS, PATHWAY, KINASE, QUANTIFICATION, IDENTIFICATION

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MLA
Mus, Liselot, et al. “The ETS Transcription Factor ETV5 Is a Target of Activated ALK in Neuroblastoma Contributing to Increased Tumour Aggressiveness.” SCIENTIFIC REPORTS, vol. 10, 2020, doi:10.1038/s41598-019-57076-5.
APA
Mus, L., Lambertz, I., Claeys, S., Kumps, C., Van Loocke, W., Van Neste, C., … Speleman, F. (2020). The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness. SCIENTIFIC REPORTS, 10. https://doi.org/10.1038/s41598-019-57076-5
Chicago author-date
Mus, Liselot, Irina Lambertz, Shana Claeys, Candy Kumps, Wouter Van Loocke, Christophe Van Neste, Ganesh Umapathy, et al. 2020. “The ETS Transcription Factor ETV5 Is a Target of Activated ALK in Neuroblastoma Contributing to Increased Tumour Aggressiveness.” SCIENTIFIC REPORTS 10. https://doi.org/10.1038/s41598-019-57076-5.
Chicago author-date (all authors)
Mus, Liselot, Irina Lambertz, Shana Claeys, Candy Kumps, Wouter Van Loocke, Christophe Van Neste, Ganesh Umapathy, Marica Vaapil, Christoph Bartenhagen, Genevieve Laureys, Olivier De Wever, Daniel Bexell, Matthias Fischer, Bengt Hallberg, Johannes Schulte, Bram De Wilde, Kaat Durinck, Geertrui Denecker, Katleen De Preter, and Franki Speleman. 2020. “The ETS Transcription Factor ETV5 Is a Target of Activated ALK in Neuroblastoma Contributing to Increased Tumour Aggressiveness.” SCIENTIFIC REPORTS 10. doi:10.1038/s41598-019-57076-5.
Vancouver
1.
Mus L, Lambertz I, Claeys S, Kumps C, Van Loocke W, Van Neste C, et al. The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness. SCIENTIFIC REPORTS. 2020;10.
IEEE
[1]
L. Mus et al., “The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness,” SCIENTIFIC REPORTS, vol. 10, 2020.
@article{8643885,
  abstract     = {{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.}},
  articleno    = {{218}},
  author       = {{Mus, Liselot and Lambertz, Irina and Claeys, Shana and Kumps, Candy and Van Loocke, Wouter and Van Neste, Christophe and Umapathy, Ganesh and Vaapil, Marica and Bartenhagen, Christoph and Laureys, Genevieve and De Wever, Olivier and Bexell, Daniel and Fischer, Matthias and Hallberg, Bengt and Schulte, Johannes and De Wilde, Bram and Durinck, Kaat and Denecker, Geertrui and De Preter, Katleen and Speleman, Franki}},
  issn         = {{2045-2322}},
  journal      = {{SCIENTIFIC REPORTS}},
  keywords     = {{UP-REGULATION,RNA-SEQ,EXPRESSION,MYCN,DIFFERENTIATION,NEURONS,PATHWAY,KINASE,QUANTIFICATION,IDENTIFICATION}},
  language     = {{eng}},
  pages        = {{13}},
  title        = {{The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness}},
  url          = {{http://dx.doi.org/10.1038/s41598-019-57076-5}},
  volume       = {{10}},
  year         = {{2020}},
}

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