SUN-MKL1 Crosstalk Regulates Nuclear Deformation and Fast Motility of Breast Carcinoma Cells in Fibrillar ECM Microenvironment.
SUN-MKL1 Crosstalk Regulates Nuclear Deformation and Fast Motility of Breast Carcinoma Cells in Fibrillar ECM Microenvironment.
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DOI：
10.3390/cells10061549
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发表时间：
2021-06-19
期刊：
影响因子：
6
通讯作者：
Condeelis JS
中科院分区：
文献类型：
--
作者：
Sharma VP;Williams J;Leung E;Sanders J;Eddy R;Castracane J;Oktay MH;Entenberg D;Condeelis JS
排列的胶原纤维为单个肿瘤细胞的快速迁移（流动迁移）提供了地形图，以侵入周围的基质，在肿瘤巢内向血管移动，以渗透并形成远处转移。肿瘤细胞运动的机制已经在二维背景下进行了广泛的研究，但在体内背景下的快速单肿瘤细胞运动的机制的理解仍然缺乏。在这里，我们发现体内流动的肿瘤细胞使用直径低于3 µm的胶原纤维。采用匹配体内纤维尺寸的1D迁移测定，我们发现肿瘤细胞运动性依赖于1D基底宽度，细胞在最窄的1D纤维（700 nm-2.5 µm）上移动最快和最持久。有趣的是，我们还观察到核变形的限制细胞外基质孔的情况下，在1D中的高速癌细胞迁移过程中，类似于在体内肿瘤细胞中观察到的核变形。此外，我们发现，肌动球蛋白机械对齐沿着一维轴和肌动球蛋白收缩性同步调节细胞运动和核变形。为了进一步研究细胞速度与核变形之间的联系，我们专注于核骨架和细胞骨架（LINC）复合物蛋白和SRF-MKL 1信号传导的连接，机械转导，肌动球蛋白收缩性和肌动蛋白为基础的细胞运动的关键调节因子。对癌症基因组图谱数据集的分析显示，与正常组织相比，原发性肿瘤中LINC复合蛋白SUN 1和SUN 2显著减少。SUN 1 + 2 KD对LINC复合物的破坏导致多小叶延长核，增加肿瘤细胞运动性和伴随的F-肌动蛋白增加，而不影响核纤层蛋白。从机制上讲，我们发现MKL 1，细胞G-肌动蛋白与F-肌动蛋白比例变化的效应子，是SUN 1 + 2 KD细胞中观察到的增加的1D运动所必需的。因此，我们证明了一个以前未被认识到的SUN蛋白和MKL 1转录因子之间的串扰在调节核形状和癌细胞运动在体内相关的1D微环境。
Aligned collagen fibers provide topography for the rapid migration of single tumor cells (streaming migration) to invade the surrounding stroma, move within tumor nests towards blood vessels to intravasate and form distant metastases. Mechanisms of tumor cell motility have been studied extensively in the 2D context, but the mechanistic understanding of rapid single tumor cell motility in the in vivo context is still lacking. Here, we show that streaming tumor cells in vivo use collagen fibers with diameters below 3 µm. Employing 1D migration assays with matching in vivo fiber dimensions, we found a dependence of tumor cell motility on 1D substrate width, with cells moving the fastest and the most persistently on the narrowest 1D fibers (700 nm–2.5 µm). Interestingly, we also observed nuclear deformation in the absence of restricting extracellular matrix pores during high speed carcinoma cell migration in 1D, similar to the nuclear deformation observed in tumor cells in vivo. Further, we found that actomyosin machinery is aligned along the 1D axis and actomyosin contractility synchronously regulates cell motility and nuclear deformation. To further investigate the link between cell speed and nuclear deformation, we focused on the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins and SRF-MKL1 signaling, key regulators of mechanotransduction, actomyosin contractility and actin-based cell motility. Analysis of The Cancer Genome Atlas dataset showed a dramatic decrease in the LINC complex proteins SUN1 and SUN2 in primary tumor compared to the normal tissue. Disruption of LINC complex by SUN1 + 2 KD led to multi-lobular elongated nuclei, increased tumor cell motility and concomitant increase in F-actin, without affecting Lamin proteins. Mechanistically, we found that MKL1, an effector of changes in cellular G-actin to F-actin ratio, is required for increased 1D motility seen in SUN1 + 2 KD cells. Thus, we demonstrate a previously unrecognized crosstalk between SUN proteins and MKL1 transcription factor in modulating nuclear shape and carcinoma cell motility in an in vivo relevant 1D microenvironment.
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影响因子：
--
作者：
Denais C;Lammerding J
通讯作者：
Lammerding J
影响因子：
2.8
作者：
Davidson, Patricia M.;Denais, Celine;Bakshi, Maya C.;Lammerding, Jan
通讯作者：
Lammerding, Jan
DOI：
10.1083/jcb.200810041
发表时间：
2009-02-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Doyle AD;Wang FW;Matsumoto K;Yamada KM
通讯作者：
Yamada KM
影响因子：
21.3
作者：
Balaban, NQ;Schwarz, US;Geiger, B
通讯作者：
Geiger, B
影响因子：
4
作者：
Balkwill, Frances R.;Capasso, Melania;Hagemann, Thorsten
通讯作者：
Hagemann, Thorsten