文章：

靶向翻译与细胞周期对循环肿瘤细胞代谢产生相反影响但不影响转移

Targeting Translation and the Cell Cycle Inversely Affects CTC Metabolism but Not Metastasis

原文发布日期：2 November 2023

DOI: 10.3390/cancers15215263

类型: Article

开放获取: 是

英文摘要：

Melanoma brain metastasis (MBM) is significantly associated with poor prognosis and is diagnosed in 80% of patients at autopsy. Circulating tumor cells (CTCs) are “seeds” of metastasis and the smallest functional units of cancer. Our multilevel approach has previously identified a CTC RPL/RPS gene signature directly linked to MBM onset. We hypothesized that targeting ribogenesis prevents MBM/metastasis in CTC-derived xenografts. We treated parallel cohorts of MBM mice with FDA-approved protein translation inhibitor omacetaxine with or without CDK4/CDK6 inhibitor palbociclib, and monitored metastatic development and cell proliferation. Necropsies and IVIS imaging showed decreased MBM/extracranial metastasis in drug-treated mice, and RNA-Seq on mouse-blood-derived CTCs revealed downregulation of four RPL/RPS genes. However, mitochondrial stress tests and RT-qPCR showed that omacetaxine and palbociclib inversely affected glycolytic metabolism, demonstrating that dual targeting of cell translation/proliferation is critical to suppress plasticity in metastasis-competent CTCs. Equally relevant, we provide the first-ever functional metabolic characterization of patient-derived circulating neoplastic cells/CTCs.

摘要翻译： 

黑色素瘤脑转移（MBM）与不良预后显著相关，约80%的患者在尸检时确诊。循环肿瘤细胞（CTCs）是转移的“种子”，也是癌症最小的功能单元。我们先前通过多层次研究方法，鉴定出与MBM发生直接相关的CTCs中RPL/RPS基因特征。我们假设靶向核糖体生物合成可抑制CTCs来源的异种移植模型中的MBM/转移。我们使用FDA批准的蛋白质翻译抑制剂高三尖杉酯碱（omacetaxine），联合或不联合CDK4/CDK6抑制剂帕博西尼（palbociclib），对MBM小鼠平行队列进行治疗，并监测转移进展和细胞增殖。尸检及活体成像结果显示，药物治疗组小鼠的MBM及颅外转移减少；对小鼠血液来源CTCs的RNA测序分析显示四个RPL/RPS基因表达下调。然而，线粒体应激测试和RT-qPCR表明，高三尖杉酯碱与帕博西尼对糖酵解代谢产生相反的影响，这证明同时靶向细胞翻译与增殖过程对于抑制具有转移能力的CTCs的可塑性至关重要。同样重要的是，本研究首次对患者来源的循环肿瘤细胞/CTCs进行了功能性代谢特征分析。

原文链接：

Targeting Translation and the Cell Cycle Inversely Affects CTC Metabolism but Not Metastasis