前列腺癌是男性最常见的恶性肿瘤，预后相对良好。然而，当它扩散到骨头时，存活率急剧下降。骨转移的发展使患者罹患侵袭性前列腺癌，这是男性死亡的主要原因。而且，骨转移是无法治愈的，而且非常痛苦。肝细胞生长因子受体 (MET) 和编码 E26 转化特异性 (ETS) 转录因子的基因融合均参与该疾病的进展。尤其是 ETS 基因融合体能够诱导前列腺癌细胞的迁移和侵袭特性，而 MET 受体通过其信号级联反应能够激活转录因子的表达。 MET 信号传导和 ETS 基因融合与高级别前列腺癌密切相关。然而，这些因素在前列腺癌进展中的相互作用尚未得到研究。在这里，我们使用晚期前列腺癌的细胞模型表明，ETS 易位变体 1 (ETV1) 和转录调节因子 ERG (ERG) 转录因子（ETS 家族成员）可促进肿瘤特性，而 MET 信号传导的激活可增强这些作用。通过在人源化肝细胞生长因子 (HGF) 小鼠模型中使用特定的 MET 酪氨酸激酶抑制剂，我们还确定 MET 活性是 ETV1/ERG 介导的肿瘤生长所必需的。最后，通过进行比较转录组分析，我们确定了可以在这些细胞过程中发挥相关作用的靶基因。因此，我们的结果首次在前列腺癌模型中证明了 ETS 转录因子（ETV1 和 ERG）与 MET 信号传导之间的功能性相互作用，这种相互作用赋予了更具侵袭性的特性，并突出了这种联合作用的分子特征特征。© 2024 ）。约翰·威利出版的《分子肿瘤学》

Prostate cancer, the most common malignancy in men, has a relatively favourable prognosis. However, when it spreads to the bone, the survival rate drops dramatically. The development of bone metastases leaves patients with aggressive prostate cancer, the leading cause of death in men. Moreover, bone metastases are incurable and very painful. Hepatocyte growth factor receptor (MET) and fusion of genes encoding E26 transformation-specific (ETS) transcription factors are both involved in the progression of the disease. ETS gene fusions, in particular, have the ability to induce the migratory and invasive properties of prostate cancer cells, whereas MET receptor, through its signalling cascades, is able to activate transcription factor expression. MET signalling and ETS gene fusions are intimately linked to high-grade prostate cancer. However, the collaboration of these factors in prostate cancer progression has not yet been investigated. Here, we show, using cell models of advanced prostate cancer, that ETS translocation variant 1 (ETV1) and transcriptional regulator ERG (ERG) transcription factors (members of the ETS family) promote tumour properties, and that activation of MET signalling enhances these effects. By using a specific MET tyrosine kinase inhibitor in a humanised hepatocyte growth factor (HGF) mouse model, we also establish that MET activity is required for ETV1/ERG-mediated tumour growth. Finally, by performing a comparative transcriptomic analysis, we identify target genes that could play a relevant role in these cellular processes. Thus, our results demonstrate for the first time in prostate cancer models a functional interaction between ETS transcription factors (ETV1 and ERG) and MET signalling that confers more aggressive properties and highlight a molecular signature characteristic of this combined action.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.