Ban Yi, Zou Yue, Liu Yingzhuo, Lee Sharrell B, Bednarczyk Robert B, Sheng Jianting, Cao Yuliang, Wong Stephen T C, Gao Dingcheng
bioRxiv. 2024 Jun 11:2023.06.28.546927. doi: 10.1101/2023.06.28.546927.
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 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.
This study uncovers the crucial involvement of ribosome biogenesis (RiBi) in the regulation of epithelial and mesenchymal state oscillations in breast cancer cells, which plays a major role in the development of chemoresistant metastasis. By proposing a novel therapeutic strategy targeting the RiBi pathway, the study offers significant potential to enhance treatment efficacy and outcomes for patients with advanced breast cancer. This approach could help overcome the limitations of current chemotherapy options and address the complex challenges posed by EMT-mediated chemoresistance.
上皮-间质转化（EMT）对化疗耐药性有显著影响，仍是治疗晚期乳腺癌的一项关键挑战。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，即间质-上皮转化（MET），阻碍了有效治疗方法的开发。在本研究中，我们利用三转基因PyMT EMT谱系追踪模型和单细胞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过程的转变阶段，核糖体生物合成（RiBi）升高。RiBi及其随后由ERK和mTOR信号介导的新生蛋白质合成对于EMT/MET的完成至关重要。重要的是，通过基因或药理学方法抑制过度的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上皮和间质肿瘤细胞在化疗下的转移生长。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景的策略。
本研究揭示了核糖体生物合成（RiBi）在调节乳腺癌细胞上皮和间质状态振荡中的关键作用，这在化疗耐药性转移的发展中起主要作用。通过提出一种靶向RiBi途径的新型治疗策略，该研究为提高晚期乳腺癌患者的治疗效果和预后提供了巨大潜力。这种方法有助于克服当前化疗方案的局限性，并应对EMT介导的化疗耐药性带来的复杂挑战。
