Aw Yong Koh Meng, Sun Yubing, Merajver Sofia D, Fu Jianping
Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan.
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
Biophys J. 2017 Mar 28;112(6):1236-1245. doi: 10.1016/j.bpj.2017.02.012.
Phenotypic plasticity is posed to be a vital trait of cancer cells such as circulating tumor cells, allowing them to undergo reversible or irreversible switching between phenotypic states important for tumorigenesis and metastasis. While irreversible phenotypic switching can be detected by studying the genome, reversible phenotypic switching is often difficult to examine due to its dynamic nature and the lack of knowledge about its contributing factors. In this study, we demonstrate that culturing cells in different physical environments, stiff, soft, or suspension, induced a phenotypic switch in prostate cancer cells via mechanotransduction. The mechanosensitive phenotypic switching in prostate cancer cells was sustainable yet reversible even after long-term culture, demonstrating the impact of mechanical signals on prostate cancer cell phenotypes. Importantly, such a mechanotransduction-mediated phenotypic switch in prostate cancer cells was accompanied by decreased sensitivity of the cells to paclitaxel, suggesting a role of mechanotransduction in the evolution of drug resistance. Multiple signaling pathways such as p38MAPK, ERK, and Wnt were found to be involved in the mechanotransduction-induced phenotypic switching of prostate cancer cells. Given that cancer cells experience different physical environments during disease progression, this study provides useful information about the important role of mechanotransduction in cancer, and how circulating tumor cells may be capable of continuously changing their phenotypes throughout the disease process.
表型可塑性被认为是循环肿瘤细胞等癌细胞的一个重要特征，使它们能够在对肿瘤发生和转移至关重要的表型状态之间进行可逆或不可逆的转换。虽然通过研究基因组可以检测到不可逆的表型转换，但由于其动态性质以及对其影响因素缺乏了解，可逆的表型转换往往难以检测。在本研究中，我们证明在不同的物理环境（坚硬、柔软或悬浮）中培养细胞，可通过机械转导诱导前列腺癌细胞发生表型转换。前列腺癌细胞中的机械敏感型表型转换即使在长期培养后也是可持续但可逆的，这证明了机械信号对前列腺癌细胞表型的影响。重要的是，前列腺癌细胞中这种由机械转导介导的表型转换伴随着细胞对紫杉醇敏感性的降低，这表明机械转导在耐药性演变中起作用。发现多种信号通路如p38MAPK、ERK和Wnt参与了机械转导诱导的前列腺癌细胞表型转换。鉴于癌细胞在疾病进展过程中会经历不同的物理环境，本研究提供了关于机械转导在癌症中的重要作用以及循环肿瘤细胞在整个疾病过程中如何能够不断改变其表型的有用信息。
