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

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. Neuroblastoma is the most common extracranial solid paediatric tumour, accounting for 15% of all childhood cancer deaths and arises from the developing sympathetic nervous system 1. In patients with high-risk disease, 5-year event-free survival is less than 50% 2 , with survivors often suffering from severe side-effects associated with current intensive multi-modal therapies and relapse after first-line therapy 1. Recent sequencing efforts have established the mutational landscape of primary and relapsed neuroblastoma. Primary neuroblastomas, similar to other embryonic tumours, have a very low mutation burden. The 'anaplastic lymphoma kinase' (ALK) tyrosine kinase receptor is the only target with significant recurrent mutations occurring in up to 10% of sporadic cases

Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells

“…Inhibition of RAS/MAPK signaling, employing the pan-RAF inhibitor LY3009120, the MEK1/2 inhibitor trametinib, the ERK1/2 inhibitor SCH772984, or the RSK1/2/3/4 inhibitor BI-D1870, led to a loss of RET protein over time that was clearly visible at 24 h ( Figure 3 D,E). In contrast, RET protein levels were not significantly altered at 24 h in cells treated with inhibitors targeting the PI3K/AKT pathway ( Figure 3 D), suggesting that oncogenic signaling through the RAS/MAPK pathway is important to maintain RET levels in NB cells in agreement with previous findings [ 37 , 49 ].…”

“…Furthermore, a role for ETS variant transcription factor 5 (Etv5) downstream of the RAS/MAPK arm of Alk signaling was shown to be important in the regulation of Ret expression [ 37 ], in agreement with our findings here. This RAS/MAPK-dependent activation of ETV5 downstream of ALK was independently reported in NB cells [ 49 ].…”

The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution

“…The resulting S100B correlation module comprised 35 genes (at r = 0.6) all of which exhibited statistically significant DE between MIS and EM-IM (FDR < 0.05) (Figures 2H and 2I; Table S6). The module included: (i) genes such as SERPINE2 (Wu, 2016), CTSL (Sudhan et al, 2016;Sui et al, 2016), TBC1D7 (Qi et al, 2020), and NRP2 (Moriarty et al, 2016) implicated in metastasis or invasion in diverse cancers; (ii) MITF-regulated genes such as the SCD (Vivas-García et al, 2020) and CDK2 (Du et al, 2004); (iii) oncogenes, such as ETV5, an oncogenic transcription factor in prostate cancer (Jané-Valbuena et al, 2010;Mus et al, 2020).…”

Higher ETV5 Expression Associates With Poor 5-Florouracil-Based Adjuvant Therapy Response in Colon Cancer

“…We also checked the correlation between ETV5 and colon cancer cell proliferating markers (MK167, MYC, MYBL2) in order to assess the effect of ETV5 over cell proliferation. We observed that ETV5 corelates with cell proliferation markers in adjCTX treated patients in most of the datasets ( Supplementary Table S3 ) suggesting a significant role of ETV5 in cancer cell proliferation as observed in the colorectal cancer cells ( Bazzocco et al, 2015 ) and other cancer cells ( Puli et al, 2018 ; Mus et al, 2020 ).…”