复发仍然是改善乳腺癌患者结果的重要临床障碍。RON受体是所有亚型乳腺癌的转移进展和复发的预测因子。RON定向治疗正在开发中，但直接测试RON抑制对转移进展/复发影响的临床前数据不足，并且实施此功能的机制仍不清楚。在这里，我们使用种植RON过表达的小鼠乳腺癌细胞模拟乳腺癌复发。通过体内成像和外体培养从肿瘤携带的小鼠全血样品中的循环肿瘤细胞检查了手术切除后的复发生长。使用乳球体形成测定进行体外功能评估。转录组通路富集确定了在RON过表达乳腺癌细胞中富集的糖酵解和胆固醇生物合成途径、转录因子靶点和信号通路。RON抑制剂BMS777607阻止了CTC群落形成的肿瘤细胞和肿瘤复发。RON通过上调胆固醇产生利用糖酵解产生的底物促进乳球体的形成。在具有RON过表达的小鼠模型中，他汀类抑制胆固醇生物合成阻碍了转移进展和复发，但不影响原发肿瘤。RON通过两条通路上调糖酵解和胆固醇生物合成基因表达：MAPK依赖c-Myc表达和β-连环蛋白依赖SREBP2表达。 ©2023.作者在Springer Nature Limited独家许可下。

Recurrence remains a significant clinical barrier to improving breast cancer patient outcomes. The RON receptor is a predictor of metastatic progression and recurrence in breast cancers of all subtypes. RON directed therapies are in development, but preclinical data directly testing the impact of RON inhibition on metastatic progression/recurrence are lacking, and mechanisms to exert this function remain unclear. Herein, we modeled breast cancer recurrence using implantation of RON-overexpressing murine breast cancer cells. Recurrent growth was examined after tumor resection via in vivo imaging and ex vivo culture of circulating tumor cells from whole blood samples from tumor bearing mice. In vitro functional assessment of was performed using mammosphere formation assays. Transcriptomic pathway enrichment identified glycolysis and cholesterol biosynthesis pathways, transcription factor targets, and signaling pathways enriched in RON-overexpressing breast cancer cells. BMS777607, a RON inhibitor, abrogated CTC colony formation tumor cells and tumor recurrence. RON promoted mammosphere formation through upregulated cholesterol production that utilizes glycolysis-derived substrates. In mouse models with RON overexpression, statin-mediated inhibition of cholesterol biosynthesis impeded metastatic progression and recurrence but does not affect the primary tumor. RON upregulates glycolysis and cholesterol biosynthesis gene expression by two pathways: MAPK-dependent c-Myc expression and β-catenin -dependent SREBP2 expression.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.