Spatial Heterogeneity in Cytoskeletal Mechanics Response to TGF-β1 and Hypoxia Mediates Partial Epithelial-to-Meshenchymal Transition in Epithelial Ovarian Cancer Cells.
Spatial Heterogeneity in Cytoskeletal Mechanics Response to TGF-β1 and Hypoxia Mediates Partial Epithelial-to-Meshenchymal Transition in Epithelial Ovarian Cancer Cells.
复制标题
细胞骨架力学对转化生长因子-β1（TGF-β1）和缺氧反应的空间异质性介导上皮性卵巢癌细胞发生部分上皮-间充质转化 。
DOI：
10.3390/cancers15123186
复制
发表时间：
2023-06-14
期刊：
影响因子：
5.2
通讯作者：
Dawson, Michelle R.
中科院分区：
文献类型：
--
作者：
Ghosh, Deepraj;Hsu, Jeffrey;Soriano, Kylen;Pena, Carolina Mejia;Lee, Amy H.;Dizon, Don S.;Dawson, Michelle R.
了解和靶向致命的上皮性卵巢癌的一个主要挑战是疾病的异质性，包括细胞内在的物理和遗传差异以及肿瘤中空间微环境线索的差异。在这项研究中，我们表明，微环境的线索，模仿肿瘤促进方面的体内肿瘤生态位可以改变模式的集群上皮癌细胞，并诱导形成侵袭性亚群。我们根据单细胞物理特征和潜在结构蛋白组织的分析确定了入侵亚群。我们的分析强调，集群中的外周癌细胞显示出对外部线索的响应增加了侵袭性。上皮性卵巢癌（EOC）的转移进展涉及原发肿瘤中癌细胞的部分上皮向间质转化（EMT）并扩散到腹膜液中。部分由于EOC细胞的高度异质性，在高度上皮细胞中识别EMT以响应基质力学、生长因子信号传导和组织缺氧的差异是非常困难的。我们通过跟踪细胞和核形态的变化沿着细胞骨架蛋白的组织来分析不同程度的EMT。在我们的分析中，我们看到一小部分细胞对TGF-β1和缺氧处理表现出显著的反应。我们证明，EOC细胞在空间上知道他们的周围环境，在二维环境中的细胞簇的外围EOC细胞的亚群表现出更大程度的EMT。这些外周癌细胞经历部分EMT，显示间充质和上皮特征的杂交，其通常包括较少的皮质肌动蛋白和较多的核周细胞角蛋白表达。总的来说，这些数据表明，促进肿瘤的微环境条件可以在高度上皮化的成簇癌细胞的小亚群中在空间调节的背景下介导侵袭性细胞行为，所述癌细胞保持上皮特征，同时还通过部分EMT获得一些间充质性状。
One major challenge to understanding and targeting deadly epithelial ovarian cancer is the heterogeneous nature of the disease, including intrinsic physical and genetic differences in cells and differences in the spatial microenvironmental cues in the tumor. In this study, we show that microenvironmental cues that mimic tumor promoting aspects of the in vivo tumor niche can alter the pattern of clustered epithelial cancer cells and induce the formation of invasive subpopulations. We identified the invasive subpopulations based on analysis of single cell physical characteristics and underlying structural protein organization. Our analysis highlights that peripheral cancer cells in a cluster display increased invasiveness in response to the external cues. Metastatic progression of epithelial ovarian cancer (EOC) involves the partial epithelial-to-mesenchymal transition (EMT) of cancer cells in the primary tumor and dissemination into peritoneal fluid. In part to the high degree of heterogeneity in EOC cells, the identification of EMT in highly epithelial cells in response to differences in matrix mechanics, growth factor signaling, and tissue hypoxia is very difficult. We analyzed different degrees of EMT by tracking changes in cell and nuclear morphology, along with the organization of cytoskeletal proteins. In our analysis, we see a small percentage of individual cells that show dramatic response to TGF-β1 and hypoxia treatment. We demonstrate that EOC cells are spatially aware of their surroundings, with a subpopulation of EOC cells at the periphery of a cell cluster in 2D environments exhibited a greater degree of EMT. These peripheral cancer cells underwent partial EMT, displaying a hybrid of mesenchymal and epithelial characteristics, which often included less cortical actin and more perinuclear cytokeratin expression. Collectively, these data show that tumor-promoting microenvironment conditions can mediate invasive cell behavior in a spatially regulated context in a small subpopulation of highly epithelial clustered cancer cells that maintain epithelial characteristics while also acquiring some mesenchymal traits through partial EMT.
登录
查看更多内容
影响因子：
5.8
作者：
Gao J;Zhu Y;Nilsson M;Sundfeldt K
通讯作者：
Sundfeldt K
影响因子：
--
作者：
Lin HH;Lin HK;Lin IH;Chiou YW;Chen HW;Liu CY;Harn HI;Chiu WT;Wang YK;Shen MR;Tang MJ
通讯作者：
Tang MJ
DOI：
10.1097/pas.0b013e3181cf3d79
发表时间：
2010-03
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Kurman RJ;Shih IeM
通讯作者：
Shih IeM
影响因子：
4.3
作者：
Estabrook ID;Thiam HR;Piel M;Hawkins RJ
通讯作者：
Hawkins RJ
DOI：
10.1038/nrm3112
发表时间：
2011-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--