College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, PR China.
College of Chemistry, Nankai University, Tianjin, 300071, PR China.
Acta Biomater. 2024 Sep 1;185:312-322. doi: 10.1016/j.actbio.2024.06.046. Epub 2024 Jul 4.
Mutation in oncogene KRas plays a crucial role in the occurrence and progression of numerous malignant tumors. Malignancy involves changes in cell mechanics for extensive cellular deformation during metastatic dissemination. We hypothesize that oncogene KRas mutations are intrinsic to alterations in cellular mechanics that promote malignant tumor generation and progression. Here, we demonstrate the use of optical tweezers coupled with a confocal fluorescence imaging system and gene interference technique to reveal that the mutant KRas protein can be transported between homogeneous and heterogeneous tumor cells by tunneling nanotubes (TNTs), resulting in a significant reduction of membrane tension and acceleration of membrane phospholipid flow in the recipient cells. Simultaneously, the changes in membrane mechanical properties of the tumor cells also enhance the metastatic and invasive ability of the tumors, which further contribute to the deterioration of the tumors. This finding helps to clarify the association between oncogene mutations and changes in the mechanical properties of tumor cells, which provides a theoretical basis for the development of cancer treatment strategies. STATEMENT OF SIGNIFICANCE: Here, we present a laser confocal fluorescence system integrated with optical tweezers to observe the transfer of mutant KRas protein from mutant cells to wild-type cells through TNTs. Malignancy involves changes in cell mechanics for extensive cellular deformation during metastatic dissemination. Our results demonstrate a significant decrease in membrane tension and an increase in membrane phospholipid flow in recipient cells. These alterations in mechanical properties augment the migration and invasive capabilities of tumor cells, contributing to tumor malignancy. Our findings propose that cellular mechanical properties could serve as new markers for tumor development, and targeting membrane tension may hold potential as a therapeutic strategy.
癌基因 KRas 突变在许多恶性肿瘤的发生和发展中起着至关重要的作用。恶性肿瘤涉及细胞力学的变化，以在转移传播过程中进行广泛的细胞变形。我们假设癌基因 KRas 突变是促进恶性肿瘤发生和发展的细胞力学变化的内在因素。在这里，我们展示了使用光学镊子结合共聚焦荧光成像系统和基因干扰技术，揭示突变 KRas 蛋白可以通过隧道纳米管（TNTs）在同质和异质肿瘤细胞之间运输，导致膜张力显著降低和受纳细胞中膜磷脂流加速。同时，肿瘤细胞的膜力学性质的变化也增强了肿瘤的转移和侵袭能力，这进一步导致了肿瘤的恶化。这一发现有助于阐明癌基因突变与肿瘤细胞力学性质变化之间的联系，为癌症治疗策略的发展提供了理论依据。
在这里，我们提出了一种将光学镊子与激光共聚焦荧光系统集成的方法，用于观察突变 KRas 蛋白通过 TNTs 从突变细胞转移到野生型细胞。恶性肿瘤涉及细胞力学的变化，以在转移传播过程中进行广泛的细胞变形。我们的结果表明，受纳细胞中的膜张力显著降低，膜磷脂流增加。这些力学性质的改变增强了肿瘤细胞的迁移和侵袭能力，导致肿瘤恶性。我们的发现表明，细胞力学性质可以作为肿瘤发展的新标志物，靶向膜张力可能是一种有前途的治疗策略。
