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癌细胞借助机械力应答机制进行转移

摘要 : 近日,北卡罗莱纳大学Lineberger综合癌症中心的两项研究中,其中一项首次向人们展示,单独的细胞器也能应答机械力。另外一项揭示细胞对机械力应答的机制,而这一机制赋予肿瘤细胞穿过血管壁的能力。相关文章分别发表于《Nature Cell Biology》和《Journal of Immunology》杂志上。
癌细胞借助机械力应答机制进行转移

机械力是癌症和其他疾病中的一个关键性因素,为了通过机械力应答进一步理解癌症发展和癌细胞转移,Keith Burridge教授与Richard Superfine教授建立了长期的合作。他们希望解析细胞移动、变硬和应答机械压力的过程,揭示在上述过程中起作用的细胞通路。这样的信息可以帮助人们找到癌症和多种疾病的病因,开发新的治疗药物。

“机械力应答对于癌症来说是很重要的。在肿瘤细胞侵入和挤压其他细胞时,机械力的作用非常关键,”Burridge说。“肿瘤细胞会对自己附着的细胞施力,尝试离开原地向远处转移。”

Nature Cell Biology文章的第一作者Christophe Guilluy向人们展示,单独的细胞核能够对机械力做出反应。研究人员给2.8-4微米大的金属微珠连上特殊蛋白,这种蛋白能够结合在细胞核外。然后他们通过一系列磁性脉冲对金属微珠施加拉力。研究显示,每一次脉冲使细胞核移动的距离越来越小,说明细胞核在机械力的作用下变得更加坚硬。

在这项实验之前科学家们一直以为,细胞对机械力的应答源自于细胞表面以及细胞器周围的细胞骨架。“以往我们普遍认为,细胞的外围区域负责应答机械力,”Burridge说。“我们这应该是首次展示,单独的细胞器也能应答机械力。我认为这是生物学的一个重要发现。”

Journal of Immunology文章的第一作者Elizabeth Lessey-Morillon对血管内皮细胞进行了研究,揭示了免疫细胞离开血流进入周围组织的途径。癌症研究者们对这一过程特别感兴趣,因为肿瘤细胞在发生转移时也使用了同样的机制。研究人员发现,在上述一过程中血管内皮细胞有一个变硬和放松的特殊机制。

“我们认为转移中的癌细胞本质上模拟了白细胞的活动,”Burridge说。

研究人员将磁性微珠附着在血管壁的内皮细胞上,随后对这些细胞施加机械力。研究显示,机械力会使内皮细胞变硬,打开这些细胞之间的空隙,而白细胞可以从这些空隙中穿过。进一步研究指出,这种机械力应答激活了一个由RhoA和LARG蛋白介导的通路。

研究人员发现,阻断这一通路可以延缓细胞的变硬。Burridge指出,这一现象说明上述通路在癌转移中具有重要作用,可以成为未来癌症治疗的新靶标。

“在肿瘤细胞移动时,也会出现上述机械力应答。正是这一机制赋予肿瘤细胞穿过血管壁的能力,”Burridge说。

原文摘要:

Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus

Christophe Guilluy, Lukas D. Osborne, Laurianne Van Landeghem, Lisa Sharek, Richard Superfine, Rafael Garcia-Mata, Keith Burridge

Mechanical forces influence many aspects of cell behaviour. Forces are detected and transduced into biochemical signals by force-bearing molecular elements located at the cell surface, in adhesion complexes or in cytoskeletal structures1. The nucleus is physically connected to the cell surface through the cytoskeleton and the 1inker of nucleoskeleton and cytoskeleton (LINC) complex, allowing rapid mechanical stress transmission from adhesions to the nucleus2. Although it has been demonstrated that nuclei experience force3, the direct effect of force on the nucleus is not known. Here we show that isolated nuclei are able to respond to force by adjusting their stiffness to resist the applied tension. Using magnetic tweezers, we found that applying force on nesprin-1 triggers nuclear stiffening that does not involve chromatin or nuclear actin, but requires an intact nuclear lamina and emerin, a protein of the inner nuclear membrane. Emerin becomes tyrosinephosphorylated in response to force and mediates the nuclear mechanical response to tension. Our results demonstrate that mechanotransduction is not restricted to cell surface receptors and adhesions but can occur in the nucleus.

The RhoA Guanine Nucleotide Exchange Factor, LARG, Mediates ICAM-1-Dependent Mechanotransduction in Endothelial Cells To Stimulate Transendothelial Migration

E. C. Lessey-Morillon, L. D. Osborne, E. Monaghan-Benson, C. Guilluy, E. T. O'Brien, R. Superfine, K. Burridge

RhoA-mediated cytoskeletal rearrangements in endothelial cells (ECs) play an active role in leukocyte transendothelial cell migration (TEM), a normal physiological process in which leukocytes cross the endothelium to enter the underlying tissue. Although much has been learned ab0ut RhoA signaling pathways downstream from ICAM-1 in ECs, little is known ab0ut the consequences of the tractional forces that leukocytes generate on ECs as they migrate over the surface before TEM. We have found that after applying mechanical forces to ICAM-1 clusters, there is an increase in cellular stiffening and enhanced RhoA signaling compared with ICAM-1 clustering alone. We have identified that leukemia-associated Rho guanine nucleotide exchange factor (LARG), also known as Rho GEF 12 (ARHGEF12) acts downstream of clustered ICAM-1 to increase RhoA activity, and that this pathway is further enhanced by mechanical force on ICAM-1. Depletion of LARG decreases leukocyte crawling and inhibits TEM. To our knowledge, this is the first report of endothelial LARG regulating leukocyte behavior and EC stiffening in response to tractional forces generated by leukocytes.

 

来源: 测序中国 浏览次数:172

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