Quiescent cancer cells induced by high-density cultivation reveals cholesterol-mediated survival and lung metastatic traits.

Autor: Liu X; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China., Min Q; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China., Cheng X; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China., Zhang W; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China., Wu Q; 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., Chen X; 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., Lv M; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China., Liu S; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China., Zhao H; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China., Yang D; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China., Tai Y; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China., Lei X; Peking University International Cancer Institute, 100191, Beijing, China., Wang Y; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China. wy305@126.com.; 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. wy305@126.com., Zhan Q; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100142, Beijing, China. zhanqimin@bjmu.edu.cn.; 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. zhanqimin@bjmu.edu.cn.; Peking University International Cancer Institute, 100191, Beijing, China. zhanqimin@bjmu.edu.cn.; Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China. zhanqimin@bjmu.edu.cn.; Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, 100730, Beijing, China. zhanqimin@bjmu.edu.cn.; Soochow University Cancer Institute, Suzhou, 215000, China. zhanqimin@bjmu.edu.cn.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2024 Oct 11. Date of Electronic Publication: 2024 Oct 11.
DOI: 10.1038/s41416-024-02861-x
Abstrakt: Background: 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.
Method: 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.
Result: 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.
Conclusion: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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