癌细胞通过 CKAP4 相分离介导的微管分支感知固体压力以促进转移。

IF 13 1区 生物学 Q1 CELL BIOLOGY
Xing Sun, Yangyang Zhou, Shengjie Sun, Siyuan Qiu, Menglan Peng, Han Gong, Junxiao Guo, Chengcai Wen, Yibin Zhang, Yifang Xie, Hui Li, Long Liang, Guoyan Luo, Wencan Wu, Jing Liu, Weihong Tan, Mao Ye
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引用次数: 0

摘要

来自细胞外基质和细胞的刚性和弹性成分的固体应力是肿瘤的典型物理特征。越来越多的证据表明,固体应力的升高会促使肿瘤转移并影响预后。然而,癌细胞如何感知固体应力,从而加剧恶性程度的分子机制仍不清楚。在这项研究中,我们的临床数据表明,转移性实体瘤中应激的升高与细胞骨架相关蛋白4(CKAP4)的表达高度相关。耐人寻味的是,CKAP4 作为一种敏感的细胞内机械传感器,能通过液-液相分离对所研究的肿瘤微环境要素子集中的固体应力做出特异性反应。这些微米级的CKAP4点状突起紧紧地附着在微管上,并显著地重新协调微管的弯曲和分支,以增强细胞的扩散,从而提高癌细胞的运动能力,促进体内的远处转移。从机理上讲,CKAP4的本征无序区1(IDR1)与微管结合,而IDR2则由于依赖Cav1.2的钙离子流入而控制相分离,从而共同重塑微管。这些发现揭示了一种前所未有的机制,即癌细胞如何感知固体应力以导致癌症恶变,并弥合了癌症物理学与癌细胞生物学之间的差距。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching.

Solid stress, originating from rigid and elastic components of extracellular matrix and cells, is a typical physical hallmark of tumors. Mounting evidence indicates that elevated solid stress drives metastasis and affects prognosis. However, the molecular mechanism of how cancer cells sense solid stress, thereby exacerbating malignancy, remains elusive. In this study, our clinical data suggest that elevated stress in metastatic solid tumors is highly associated with the expression of cytoskeleton-associated protein 4 (CKAP4). Intriguingly, CKAP4, as a sensitive intracellular mechanosensor, responds specifically to solid stress in a subset of studied tumor micro-environmental elements through liquid-liquid phase separation. These micron-scaled CKAP4 puncta adhere tightly onto microtubules and dramatically reorchestrate their curvature and branching to enhance cell spreading, which, as a result, boosts cancer cell motility and facilitates distant metastasis in vivo. Mechanistically, the intrinsically disordered region 1 (IDR1) of CKAP4 binds to microtubules, while IDR2 governs phase separation due to the Cav1.2-dependent calcium influx, which collectively remodels microtubules. These findings reveal an unprecedented mechanism of how cancer cells sense solid stress for cancer malignancy and bridge the gap between cancer physics and cancer cell biology.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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