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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.

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