Molter Clayton W, Muszynski Eliana F, Tao Yuanyuan, Trivedi Tanisha, Clouvel Anna, Ehrlicher Allen J
Department of Bioengineering, McGill University, Montreal, QC, Canada.
Department of Neuroscience, McGill University, Montreal, QC, Canada.
Front Cell Dev Biol. 2022 Sep 19;10:932510. doi: 10.3389/fcell.2022.932510. eCollection 2022.
During metastasis, all cancer types must migrate through crowded multicellular environments. Simultaneously, cancers appear to change their biophysical properties. Indeed, cell softening and increased contractility are emerging as seemingly ubiquitous biomarkers of metastatic progression which may facilitate metastasis. Cell stiffness and contractility are also influenced by the microenvironment. Stiffer matrices resembling the tumor microenvironment cause metastatic cells to contract more strongly, further promoting contractile tumorigenic phenotypes. Prostate cancer (PCa), however, appears to deviate from these common cancer biophysics trends; aggressive metastatic PCa cells appear stiffer, rather than softer, to their lowly metastatic PCa counterparts. Although metastatic PCa cells have been reported to be more contractile than healthy cells, how cell contractility changes with increasing PCa metastatic potential has remained unknown. Here, we characterize the biophysical changes of PCa cells of various metastatic potential as a function of microenvironment stiffness. Using a panel of progressively increasing metastatic potential cell lines (22RV1, LNCaP, DU145, and PC3), we quantified their contractility using traction force microscopy (TFM), and measured their cortical stiffness using optical magnetic twisting cytometry (OMTC) and their motility using time-lapse microscopy. We found that PCa contractility, cell stiffness, and motility do not universally scale with metastatic potential. Rather, PCa cells of various metastatic efficiencies exhibit unique biophysical responses that are differentially influenced by substrate stiffness. Despite this biophysical diversity, this work concludes that mechanical microenvironment is a key determinant in the biophysical response of PCa with variable metastatic potentials. The mechanics-oriented focus and methodology of the study is unique and complementary to conventional biochemical and genetic strategies typically used to understand this disease, and thus may usher in new perspectives and approaches.
在转移过程中，所有癌症类型都必须在拥挤的多细胞环境中迁移。同时，癌症似乎会改变其生物物理特性。事实上，细胞软化和收缩性增加正逐渐成为转移进展中似乎普遍存在的生物标志物，这可能会促进转移。细胞硬度和收缩性也受微环境影响。类似于肿瘤微环境的更硬基质会使转移细胞收缩更强，进一步促进具有收缩性的致瘤表型。然而，前列腺癌（PCa）似乎偏离了这些常见的癌症生物物理学趋势；侵袭性转移性PCa细胞与其低转移性PCa对应物相比，显得更硬而非更软。尽管有报道称转移性PCa细胞比健康细胞更具收缩性，但随着PCa转移潜能增加，细胞收缩性如何变化仍不清楚。在此，我们将不同转移潜能的PCa细胞的生物物理变化表征为微环境硬度的函数。使用一组转移潜能逐渐增加的细胞系（22RV1、LNCaP、DU145和PC3），我们使用牵引力显微镜（TFM）量化它们的收缩性，使用光磁扭细胞术（OMTC）测量它们的皮质硬度，并使用延时显微镜观察它们的运动性。我们发现PCa的收缩性、细胞硬度和运动性并不普遍随转移潜能而变化。相反，不同转移效率的PCa细胞表现出独特的生物物理反应，这些反应受到底物硬度的不同影响。尽管存在这种生物物理多样性，但这项工作得出结论，机械微环境是具有不同转移潜能的PCa生物物理反应的关键决定因素。该研究以力学为导向的重点和方法是独特的，并且是对通常用于理解这种疾病的传统生化和遗传策略的补充，因此可能会带来新的观点和方法。
