Mus, Liselot M., Lambertz, Irina, Claeys, Shana, Kumps, Candy, Van Loocke, Wouter, Van Neste, Christophe ORCID: 0000-0002-5958-5731, 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 and Speleman, Frank (2020). The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness. Sci Rep, 10 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mus, Liselot M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lambertz, IrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claeys, ShanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kumps, CandyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Loocke, WouterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Neste, ChristopheUNSPECIFIEDorcid.org/0000-0002-5958-5731UNSPECIFIED
Umapathy, GaneshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaapil, MaricaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartenhagen, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laureys, GenevieveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Wever, OlivierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bexell, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallberg, BengtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Wilde, BramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Durinck, KaatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denecker, GeertruiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Preter, KatleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speleman, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-348890
DOI: 10.1038/s41598-019-57076-5
Journal or Publication Title: Sci Rep
Volume: 10
Number: 1
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2045-2322
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
UP-REGULATION; RNA-SEQ; EXPRESSION; MYCN; DIFFERENTIATION; NEURONS; PATHWAY; KINASE; QUANTIFICATION; IDENTIFICATIONMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34889

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