The intrinsic biomechanical properties of cancer cells remain poorly understood. To decipher whether cell stiffness modulation could increase melanoma cells’ invasive capacity, we performed both in vitro and in vivo experiments exploring cell stiffness by atomic force microscopy (AFM). We correlated stiffness properties with cell morphology adaptation and the molecular mechanisms underlying epithelial-to-mesenchymal (EMT)-like phenotype switching. We found that melanoma cell stiffness reduction was systematically associated with the acquisition of invasive properties in cutaneous melanoma cell lines, human skin reconstructs, and Medaka fish developing spontaneous MAP-kinase-induced melanomas. We observed a systematic correlation of stiffness modulation with cell morphological changes towards mesenchymal characteristic gains. We accordingly found that inducing melanoma EMT switching by overexpressing the ZEB1 transcription factor, a major regulator of melanoma cell plasticity, was sufficient to decrease cell stiffness and transcriptionally induce tetraspanin-8-mediated dermal invasion. Moreover, ZEB1 expression correlated with Tspan8 expression in patient melanoma lesions. Our data suggest that intrinsic cell stiffness could be a highly relevant marker for human cutaneous melanoma development.
癌细胞的内在生物力学特性至今仍未得到充分认识。为探究细胞刚度调节能否增强黑色素瘤细胞的侵袭能力，我们通过原子力显微镜技术开展了体外与体内实验，系统研究了细胞刚度变化。我们将刚度特性与细胞形态适应性及上皮-间质转化样表型转换的分子机制进行关联分析。研究发现，在皮肤黑色素瘤细胞系、人工皮肤重建模型以及自发MAP激酶诱导黑色素瘤的青鳉鱼模型中，黑色素瘤细胞刚度降低均与侵袭性特征的获得存在系统性关联。我们观察到刚度调节与细胞形态向间质特征转变存在系统性相关。进一步研究发现，通过过表达黑色素瘤细胞可塑性的关键调控因子ZEB1转录因子诱导上皮-间质转化，足以降低细胞刚度并转录激活四跨膜蛋白-8介导的真皮侵袭过程。此外，在患者黑色素瘤病灶中，ZEB1表达与Tspan8表达呈正相关。本研究提示，细胞内在刚度可能成为人类皮肤黑色素瘤发展的关键生物标志物。
Cancer Cell Biomechanical Properties Accompany Tspan8-Dependent Cutaneous Melanoma Invasion
肿瘤(癌症)患者之家