Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
Br J Cancer. 2024 Nov;131(10):1591-1604. doi: 10.1038/s41416-024-02861-x. Epub 2024 Oct 11.
The metastatic cascade, a multifaceted and highly aggressive process, is the primary cause of mortality. The survival of quiescent cancer cells in circulatory system during metastasis is crucial, yet our comprehension is constrained by the absence of universally accepted quiescent cancer models.
We developed a quiescent cancer cell model using high-density cultivation. Based on the scRNA-seq analysis, IP-MS, metabolomics, mouse lung metastasis models, cholesterol assay, PLA and other molecular experiments, we explored the molecular mechanism. Immunofluorescence, atomic force microscope, FluidFM, and shear stress stimulation were used to analyze the cytoskeleton and membrane properties contributing to mechanical force resistance.
We established a quiescent cancer cell model induced by high-density cultivation. Single-cell RNA sequencing (scRNA-seq) analysis reveals that CDC25A plays a crucial role in the transition to quiescence, with its expression significantly elevated in the quiescent state. Depletion of CDC25A leads to an increased proliferative capacity, and reduced metastasis under high-density conditions. Mechanistically, upregulated CDC25A in quiescent cells enhances cholesterol metabolism via endosome pathways, leading to cell cycle arrest. This increase in cholesterol reinforces the cytoskeleton, alters membrane properties, and improves resistance to mechanical forces in circulatory system.
CDC25A significantly increased the cholesterol metabolism through endosome pathway in quiescent cancer cells, leading to the significant changes in cytoskeleton and membrane properties so as to enhance the resistance of mechanical force in circulatory system, facilitating lung metastasis. In high-density cultivation, quiescent cancer cells, up-regulate cholesterol metabolism by CDC25A through endosome pathway, enhancing the resistance to mechanical force in circulatory system, facilitating lung metastasis.
转移级联是一个多方面且高度侵袭性的过程，是导致死亡的主要原因。转移过程中静止癌细胞在循环系统中的存活至关重要，但由于缺乏普遍接受的静止癌细胞模型，我们的理解受到限制。
我们使用高密度培养建立了静止癌细胞模型。基于 scRNA-seq 分析、IP-MS、代谢组学、小鼠肺转移模型、胆固醇测定、PLA 等分子实验，我们探索了分子机制。免疫荧光、原子力显微镜、FluidFM 和切应力刺激用于分析有助于抵抗机械力的细胞骨架和膜特性。
我们建立了一种由高密度培养诱导的静止癌细胞模型。单细胞 RNA 测序（scRNA-seq）分析表明，CDC25A 在向静止状态的转变中起关键作用，其表达在静止状态下显著升高。CDC25A 的耗竭导致增殖能力增加，在高密度条件下转移减少。在机制上，静止细胞中上调的 CDC25A 通过内体途径增强胆固醇代谢，导致细胞周期停滞。这种胆固醇的增加增强了细胞骨架，改变了膜特性，并提高了循环系统中抵抗机械力的能力。
CDC25A 通过内体途径显著增加静止癌细胞中的胆固醇代谢，导致细胞骨架和膜特性发生显著变化，从而增强循环系统中的机械力抵抗能力，促进肺转移。在高密度培养中，静止癌细胞通过内体途径上调胆固醇代谢，增强循环系统中的机械力抵抗能力，促进肺转移。
