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以核糖体生物发生为靶点，作为一种新的治疗方法来克服乳腺癌中 EMT 相关的化疗耐药性。

Targeting ribosome biogenesis as a novel therapeutic approach to overcome EMT-related chemoresistance in breast cancer.

机构信息

Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, United States.

Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, United States.

出版信息

Elife. 2024 Sep 11;12:RP89486. doi: 10.7554/eLife.89486.

DOI:10.7554/eLife.89486
PMID:39259576
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11390108/
Abstract

Epithelial-to-mesenchymal transition (EMT) contributes significantly to chemotherapy resistance and remains a critical challenge in treating advanced breast cancer. The complexity of EMT, involving redundant pro-EMT signaling pathways and its paradox reversal process, mesenchymal-to-epithelial transition (MET), has hindered the development of effective treatments. In this study, we utilized a Tri-PyMT EMT lineage-tracing model in mice and single-cell RNA sequencing (scRNA-seq) to comprehensively analyze the EMT status of tumor cells. Our findings revealed elevated ribosome biogenesis (RiBi) during the transitioning phases of both EMT and MET processes. RiBi and its subsequent nascent protein synthesis mediated by ERK and mTOR signalings are essential for EMT/MET completion. Importantly, inhibiting excessive RiBi genetically or pharmacologically impaired the EMT/MET capability of tumor cells. Combining RiBi inhibition with chemotherapy drugs synergistically reduced metastatic outgrowth of epithelial and mesenchymal tumor cells under chemotherapies. Our study suggests that targeting the RiBi pathway presents a promising strategy for treating patients with advanced breast cancer.

摘要

上皮-间充质转化（EMT）在化疗耐药中起重要作用，仍然是治疗晚期乳腺癌的关键挑战。EMT 的复杂性，涉及冗余的促 EMT 信号通路及其矛盾的逆转过程，间质-上皮转化（MET），阻碍了有效治疗的发展。在这项研究中，我们利用三 PyMT EMT 谱系追踪模型在小鼠和单细胞 RNA 测序（scRNA-seq）全面分析肿瘤细胞的 EMT 状态。我们的研究结果显示，在 EMT 和 MET 过程的过渡阶段，核糖体生物发生（RiBi）水平升高。RiBi 及其随后由 ERK 和 mTOR 信号介导的新生蛋白合成对于 EMT/MET 的完成至关重要。重要的是，通过遗传或药理学抑制过度的 RiBi 会损害肿瘤细胞的 EMT/MET 能力。将 RiBi 抑制与化疗药物联合使用可协同减少化疗后上皮和间充质肿瘤细胞的转移生长。我们的研究表明，靶向 RiBi 途径为治疗晚期乳腺癌患者提供了一种有前途的策略。

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