细胞外流体粘度增强细胞迁移和癌症扩散
Kaustav Bera1,2, Alexander Kiepas1,2, Inês Godet1,3
1Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
Nature
|November 3, 2022
概括
通过诱导机械变化,增加细胞外液粘度会增强癌细胞的运动性和传播. 癌细胞发展出TRPV4依赖的机械记忆,促进长期的迁移和殖民.
科学领域:
- 细胞生物学
- 生物物理
- 癌症研究
背景情况:
- 细胞会感知硬度和剪切压力等物理信号.
- 细胞外液粘度是包括癌症在内的生理和病理状态的关键物理因素.
- 粘度对癌症生物学和细胞感应机制的影响在很大程度上是未知的.
研究的目的:
- 研究细胞外粘度如何影响癌细胞的行为.
- 解释细胞感知和响应粘度变化的分子机制.
- 探索粘度对癌细胞特性和转移潜力的长期影响.
主要方法:
- 在二维表面和封闭中使用细胞培养,以及3D瘤球体.
- 研究了行为细胞骨,ARP2/3复合体和埃兹林的作用.
- 分析了Na+/H+交换器1 (NHE1),TRPV4通道和RHOA信号的参与.
- 检查了转录的变化,包括Hippo路径,以响应粘度.
- 在体内评估细胞迁移,传播和殖民模式 (斑马鱼,小胚胎,小鼠).
主要成果:
- 这种高粘度有悖论地增加了瘤细胞的移动性和扩散.
- 由于粘度而增加的机械负荷会触发ARP2/3依赖的行为网络.
- 这种网络增强了NHE1的两极分化,导致细胞胀和膜张力.
- 激活TRPV4通道调解的流入,促进RHOA依赖的收缩性和运动性.
- 对粘度的预暴露会在乳腺癌细胞中诱导TRPV4依赖的机械记忆,增强它们的转移能力.
结论:
- 细胞外粘度是细胞运动和癌症进展的重要物理调节剂.
- 一个涉及actin,NHE1,TRPV4和RHOA的新型机械传导途径调解了对粘度的反应.
- 癌细胞中粘度诱导的机械记忆有助于长期转移潜力增加.
- 了解这些机制为癌症转移中的物理瘤微环境提供了新的见解.
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