Abstract
Cancer cells are in vivo situated in a complex and heterogeneous tumor microenvironment (TME) that includes various biochemical and biophysical cues, such as the elasticity of extracellular matrix (ECMwo) and the viscosity of extracellular fluid (ECF). ECF viscosity in TME is much higher than in normal tissue, but it is unclear how this increased viscosity works simultaneously with other biophysical cues (e.g., ECM stiffness) to influence cancer cell behavior. We experimentally observed that ECF viscosity can significantly enhance cellular mechanosensing behaviors (e.g., cell spreading, cell adhesion, and YAP/TAZ nuclear translocation) only on a stiff substrate, representing a novel enhancement of cell behaviors by distinct mechanical signals. To explore the mechanical mechanisms behind such enhancement phenomenon, we developed a viscosity-based motor-clutch model, with which we found that cells sense and respond to ECF viscosity and ECM stiffness by regulating integrin-ECM bonds in cell adhesion dynamics. These findings help us understand how different mechanical signals in the complex tumor microenvironment collaborate to influence cancer cell behaviors during the development of cancers.
摘要
体内的癌细胞处于一个复杂和异质的肿瘤微环境(TME)中, 其中包括各种生物化学和生物物理信号, 如细胞外基质(ECM)的弹性和细胞外液(ECF)的黏度. TME中的ECF黏度远高于正常组织, 但目前还不清楚这种高黏度环境如何与其它生物物理信号(如ECM硬度)同时影响癌细胞的行为. 我们通过实验观察到, ECF黏度仅在坚硬的基底上才能显著增强细胞的力学信号传感行为(如细胞铺展、细胞黏附和YAP/TAZ核转移), 这代表了一种通过不同机械信号增强细胞行为的新方法. 为了探索这种增强现象背后的力学机制, 我们建立了一个基于黏度的马达离合器模型, 我们发现细胞通过调节细胞黏附动力学中的整合素-ECM键来感知和响应ECF黏度和ECM硬度. 这些发现有助于我们理解复杂的肿瘤微环境中不同的机械信号如何在癌症发展过程中共同影响癌细胞的行为.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant Nos. 12002262, 11972280, and 12225208).
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Feng Xu and Bo Cheng designed the paper framework. Bo Cheng and Zhao Xu constructed the computational model. Chunyu Cao performed the experiment. Yan Liu contributed to the interpretation of the results. All authors analyzed the data, discussed the results, and wrote the manuscript.
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Cao, C., Xu, Z., Liu, Y. et al. Enhancement effects of extracellular fluid viscosity and matrix stiffness on cancer cell mechanosensing. Acta Mech. Sin. 39, 223238 (2023). https://doi.org/10.1007/s10409-023-23238-x
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DOI: https://doi.org/10.1007/s10409-023-23238-x