Institute of Biomedical Engineering and Health Sciences, Changzhou University, Changzhou, Jiangsu, People's Republic of China.
Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, USA.
BMC Mol Cell Biol. 2022 Jan 3;23(1):1. doi: 10.1186/s12860-021-00401-6.
Uncontrolled growth in solid breast cancer generates mechanical compression that may drive the cancer cells into a more invasive phenotype, but little is known about how such compression affects the key events and corresponding regulatory mechanisms associated with invasion of breast cancer cells including cellular behaviors and matrix degradation.
Here we show that compression enhanced invasion and matrix degradation of breast cancer cells. We also identified Piezo1 as the putative mechanosensitive cellular component that transmitted compression to not only enhance the invasive phenotype, but also induce calcium influx and downstream Src signaling. Furthermore, we demonstrated that Piezo1 was mainly localized in caveolae, and both Piezo1 expression and compression-enhanced invasive phenotype of the breast cancer cells were reduced when caveolar integrity was compromised by either knocking down caveolin1 expression or depleting cholesterol content.
Taken together, our data indicate that mechanical compression activates Piezo1 channels to mediate enhanced breast cancer cell invasion, which involves both cellular events and matrix degradation. This may be a critical mechanotransduction pathway during breast cancer metastasis, and thus potentially a novel therapeutic target for the disease.
实体乳腺癌的失控生长会产生机械压迫，可能促使癌细胞向更具侵袭性的表型转变，但人们对这种压迫如何影响与乳腺癌细胞侵袭相关的关键事件和相应的调节机制知之甚少，包括细胞行为和基质降解。
我们发现，压缩增强了乳腺癌细胞的侵袭和基质降解。我们还鉴定出 Piezo1 是一种假定的机械敏感细胞成分，它不仅能传递压缩以增强侵袭表型，还能诱导钙内流和下游Src 信号转导。此外，我们证明 Piezo1 主要定位于质膜穴样内陷（caveolae）中，当通过敲低质膜窖蛋白 1（caveolin1）的表达或耗尽胆固醇含量来破坏质膜窖完整性时，乳腺癌细胞中 Piezo1 的表达和压缩增强的侵袭表型都会降低。
综上所述，我们的数据表明，机械压迫激活 Piezo1 通道，介导增强的乳腺癌细胞侵袭，这涉及细胞事件和基质降解。这可能是乳腺癌转移过程中的一个关键力学转导途径，因此可能是该疾病的一个新的治疗靶点。
