The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation.
The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation.
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DOI：
10.1038/s41598-018-25589-0
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发表时间：
2018-05-08
影响因子：
4.6
通讯作者：
Howe AK
中科院分区：
文献类型：
--
作者：
McKenzie AJ;Hicks SR;Svec KV;Naughton H;Edmunds ZL;Howe AK
肿瘤微环境的机械特性对疾病进展的重要性越来越受到重视。然而，细胞外基质（ECM）硬度和细胞机械转导在上皮性卵巢癌（EOC）中的作用在很大程度上是未知的。在这里，我们研究了基板刚性对SKOV3人EOC细胞形态和迁移的各个方面的影响。正常小鼠腹膜，EOC转移的主要靶组织的杨氏模量值，通过原子力显微镜（AFM）测定和水凝胶制造模拟这些值。我们发现，细胞铺展，粘着斑形成，肌球蛋白轻链磷酸化，和细胞牵引力都增加了较硬的矩阵。基质刚性也正调控随机细胞迁移，重要的是，基质张力的定向增加促进SKOV3细胞硬旋转。基质刚性还促进YAP 1的核转位，YAP 1是与侵袭性转移性EOC相关的致癌转录因子。此外，多细胞EOC球体的解聚，与传播和转移相关的行为，通过涉及ROCK，肌动球蛋白收缩性和FAK的机械转导途径通过基质硬度增强。最后，这种机械敏感性模式在高转移性SKOV3ip.1细胞中得以维持。这些结果表明，肿瘤微环境的机械特性可能在EOC转移中发挥作用。
There is growing appreciation of the importance of the mechanical properties of the tumor microenvironment on disease progression. However, the role of extracellular matrix (ECM) stiffness and cellular mechanotransduction in epithelial ovarian cancer (EOC) is largely unknown. Here, we investigated the effect of substrate rigidity on various aspects of SKOV3 human EOC cell morphology and migration. Young’s modulus values of normal mouse peritoneum, a principal target tissue for EOC metastasis, were determined by atomic force microscopy (AFM) and hydrogels were fabricated to mimic these values. We find that cell spreading, focal adhesion formation, myosin light chain phosphorylation, and cellular traction forces all increase on stiffer matrices. Substrate rigidity also positively regulates random cell migration and, importantly, directional increases in matrix tension promote SKOV3 cell durotaxis. Matrix rigidity also promotes nuclear translocation of YAP1, an oncogenic transcription factor associated with aggressive metastatic EOC. Furthermore, disaggregation of multicellular EOC spheroids, a behavior associated with dissemination and metastasis, is enhanced by matrix stiffness through a mechanotransduction pathway involving ROCK, actomyosin contractility, and FAK. Finally, this pattern of mechanosensitivity is maintained in highly metastatic SKOV3ip.1 cells. These results establish that the mechanical properties of the tumor microenvironment may play a role in EOC metastasis.