Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul 06974, South Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul 06974, South Korea.
Department of Urology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul 06974, South Korea.
Life Sci. 2022 Nov 1;308:120936. doi: 10.1016/j.lfs.2022.120936. Epub 2022 Sep 6.
Mechanical forces surrounding solid tumors are pervasive in the tumor microenvironment (TME) and abnormally altered as solid tumors progress. Although it has been reported that biomechanical forces, including wall shear stress (WSS), enhance the metastatic features of cancer cells, its mechanism remains unknown. Here, we investigate how cancer cells sense mechanical stress and propagate signals in the TME.
Using a microfluidic device, interstitial fluid-mimicking flow (0.05 dyne cm) was applied to the human prostate cancer cell line PC3. Piezo1 siRNA and shRNA lentivirus were applied to PC3 cells to ablate Piezo1 expression. PC3-Luc2 cells expressing control shRNA or shPiezo1 lentivirus were administered into the prostate of BALB/c mice for orthotopic injection.
Here, we show that Piezo1, a mechanosensitive ion channel, is activated by WSS in microfluidic channels. Moreover, Yoda1, a Piezo1 agonist, synergistically potentiates cancer cell motility and nuclear retention of YAP/TAZ via WSS. Also, Piezo1 increases Src phosphorylation, which activates YAP. Conversely, silencing Piezo1 significantly reduces cell motility and YAP/TAZ activity induced by WSS, and finally retards tumor growth and metastasis of administered PC3 cells in BALB/c mice.
Taken together, these results demonstrate that Piezo1 allows cancer cells to sense mechanical stimuli by altering the microenvironment during tumor progression and is a critical player in modulating cancer metastasis through the Piezo1-Src-YAP axis.
实体瘤周围的机械力在肿瘤微环境（TME）中普遍存在，并随着实体瘤的进展而异常改变。尽管已有报道称，包括壁切应力（WSS）在内的生物力学力增强了癌细胞的转移特征，但其机制尚不清楚。在这里，我们研究了癌细胞如何感知机械应激并在 TME 中传播信号。
使用微流控装置，将类似于间质液的流动（0.05 达因厘米）施加到人前列腺癌细胞系 PC3 上。应用 Piezo1 siRNA 和 shRNA 慢病毒来敲除 PC3 细胞中的 Piezo1 表达。将表达对照 shRNA 或 shPiezo1 慢病毒的 PC3-Luc2 细胞注入 BALB/c 小鼠的前列腺中进行原位注射。
在这里，我们表明，机械敏感离子通道 Piezo1 被微流控通道中的 WSS 激活。此外，Yoda1，一种 Piezo1 激动剂，通过 WSS 协同增强癌细胞的迁移能力和 YAP/TAZ 的核保留。此外，Piezo1 增加了Src 的磷酸化，从而激活了 YAP。相反，沉默 Piezo1 显著降低了 WSS 诱导的细胞迁移和 YAP/TAZ 活性，并最终抑制了给予的 PC3 细胞在 BALB/c 小鼠中的肿瘤生长和转移。
综上所述，这些结果表明，Piezo1 通过改变肿瘤进展过程中的微环境，使癌细胞能够感知机械刺激，并且是通过 Piezo1-Src-YAP 轴调节癌症转移的关键因素。
