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细胞内pH动态响应细胞外矩阵硬化,并通过β-catenin介导血管仿真
Leah M Lund1,2, Angelina N Marchi1,2,3, Laura Alderfer4,5
1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
细胞外矩阵的刚性降低了细胞内pH值 (pHi),导致癌细胞形成血管生成模拟物 (VM). 向pHi为癌症和涉及矩阵重塑的疾病提供了新的治疗策略.
科学领域:
- 癌症生物学 癌症生物学
- 细胞生物物理学 细胞生物物理学
- 机械生物学 机械生物学
背景情况:
- 不调节的细胞内pH值 (pHi) 和瘤微环境的改变驱动癌症表型.
- 微环境物理性质与细胞内信号传递之间的联系尚未得到充分理解.
研究的目的:
- 调查细胞外矩阵 (ECM) 刚性和pHi动态之间驱动血管生成模拟 (VM) 的机械联系.
- 在癌症进展中确定集成ECM刚性和pHi信号的分子媒介.
主要方法:
- 肺和乳腺转移细胞系中pHi的单细胞成像.
- 使用可调节度水凝系统 (Matrigel和酸凝) 来建模ECM的度.
- 描述了β-catenin和FOXC2在介导VM中的作用.
主要成果:
- 增加的ECM刚度降低了单细胞pHi,并促进了VM.
- 低pHi对于VM是必不可少的;在硬的ECM上,高的pHi降低了VM.
- 在柔软的ECM上降低pHi诱导VM;β-catenin介导的硬度驱动VM,而FOXC2是pHi不敏感的.
结论:
- ECM的刚性调节pHi以驱动β-catenin介导的VM,建立了一个新的机械传导轴.
- pHi动态可以覆盖机械敏感细胞反应.
- pHi在癌症中整合了机械传导,表明了治疗向潜力.
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