肝细胞癌(HCC)细胞,尤其是那些有转移能力的人,与非恶性对应物相比,显示出降低的刚度。然而,目前尚不清楚HCC细胞的机制是否以及如何影响其迁移和侵袭。这项研究报告,肝癌细胞具有增强的运动性表现出降低的机械刚度和细胞骨架,表明细胞刚度和运动之间的负相关。通过药理学和遗传学方法,抑制肌动球蛋白活性降低HCC细胞硬度,但促进其迁移和侵袭,同时激活它增加细胞硬度,但损害细胞运动。肌动球蛋白通过影响细胞硬度来调节细胞运动。机械上,削弱/加强细胞抑制/促进c-JunN末端激酶(JNK)磷酸化,其激活/抑制挽救细胞力学对其迁移和侵袭的影响。Further,HCC癌症干细胞(CSC)比对照细胞表现出更高的运动性但更低的硬度。增加CSC硬度通过激活JNK信号减弱迁移和侵袭。总之,我们的发现揭示了肌动球蛋白介导的细胞力学在肿瘤细胞运动中的新调节作用,并提供了新的证据支持肿瘤细胞软化可能是HCC转移的驱动力之一.重要性声明:肿瘤细胞在转移过程中逐渐软化,低细胞硬度与高转移潜能相关。然而,目前尚不清楚肿瘤细胞软化是否是肿瘤进展的副产品或驱动力.这项工作报告说,肝细胞癌细胞的刚度与其迁移和侵袭有关。重要的是,肿瘤细胞软化促进迁移和侵袭,而细胞变硬会损害移动性。削弱/加强细胞抑制/促进JNK磷酸化,其激活/抑制挽救了细胞力学对其迁移和侵袭能力的影响。Further,硬化肝癌干细胞通过激活JNK信号减弱其运动。总之,我们的研究揭示了肿瘤细胞力学在迁移和侵袭中以前未被重视的作用,并暗示了细胞力学在机械靶向转移中的治疗潜力.
Hepatocellular carcinoma (HCC) cells, especially those with metastatic competence, show reduced stiffness compared to the non-malignant counterparts. However, it is still unclear whether and how the mechanics of HCC cells influence their migration and invasion. This study reports that HCC cells with enhanced motility show reduced mechanical stiffness and cytoskeleton, suggesting the inverse correlation between cellular stiffness and motility. Through pharmacologic and genetic approaches, inhibiting actomyosin activity reduces HCC cellular stiffness but promotes their migration and invasion, while activating it increases cell stiffness but impairs cell motility. Actomyosin regulates cell motility through the influence on cellular stiffness. Mechanistically, weakening/strengthening cells inhibits/promotes c-Jun N terminal kinase (JNK) phosphorylation, activation/inhibition of which rescues the effects of cell mechanics on their migration and invasion. Further, HCC cancer stem cells (CSCs) exhibit higher motility but lower stiffness than control cells. Increasing CSC stiffness weakens migration and invasion through the activation of JNK signaling. In conclusion, our findings unveil a new regulatory role of actomyosin-mediated cellular mechanics in tumor cell motility and present new evidence to support that tumor cell softening may be one driving force for HCC metastasis. STATEMENT OF SIGNIFICANCE: Tumor cells progressively become softened during metastasis and low cell stiffness is associated with high metastatic potential. However, it remains unclear whether tumor cell softening is a by-product of or a driving force for tumor progression. This work reports that the stiffness of hepatocellular carcinoma cells is linked to their migration and invasion. Importantly, tumor cell softening promotes migration and invasion, while cell stiffening impairs the mobility. Weakening/strengthening cells inhibits/promotes JNK phosphorylation, activation/inhibition of which rescues the effects of cell mechanics on their migration and invasion ability. Further, stiffening liver cancer stem cells attenuates their motility through activating JNK signaling. In summary, our study uncovers a previously unappreciated role of tumor cell mechanics in migration and invasion and implicates the therapeutic potential of cell mechanics in the mechanotargeting of metastasis.