Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Cancer Biology Program, Biomedical Sciences, University of Iowa, Iowa City, IA 52242, USA.
Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, IA 52242, USA.
Cell Rep. 2020 Mar 17;30(11):3864-3874.e6. doi: 10.1016/j.celrep.2020.02.080.
During metastasis, cancer cells are exposed to potentially destructive hemodynamic forces including fluid shear stress (FSS) while en route to distant sites. However, prior work indicates that cancer cells are more resistant to brief pulses of high-level FSS in vitro relative to non-transformed epithelial cells. Herein, we identify a mechano-adaptive mechanism of FSS resistance in cancer cells. Our findings demonstrate that cancer cells activate RhoA in response to FSS, which protects them from FSS-induced plasma membrane damage. We show that cancer cells freshly isolated from mouse and human tumors are resistant to FSS, that formin and myosin II activity protects circulating tumor cells (CTCs) from destruction, and that short-term inhibition of myosin II delays metastasis in mouse models. Collectively, our data indicate that viable CTCs actively resist destruction by hemodynamic forces and are likely to be more mechanically robust than is commonly thought.
在转移过程中，癌细胞会暴露于潜在的破坏性血流动力中，包括流体切应力 (FSS)，而此时它们正在前往远处的部位。然而，之前的工作表明，与非转化上皮细胞相比，癌细胞在体外对高水平 FSS 的短暂脉冲更具有抗性。在此，我们确定了癌细胞抵抗 FSS 的机械适应性机制。我们的研究结果表明，癌细胞会对 FSS 激活 RhoA，从而保护它们免受 FSS 引起的细胞膜损伤。我们表明，从小鼠和人类肿瘤中新鲜分离的癌细胞对 FSS 具有抗性，形成蛋白和肌球蛋白 II 活性可保护循环肿瘤细胞 (CTC) 免受破坏，并且短期抑制肌球蛋白 II 可延迟小鼠模型中的转移。总的来说，我们的数据表明，存活的 CTC 积极抵抗血流动力的破坏，并且可能比通常认为的更具机械强度。
