Isolating and targeting the real-time plasticity and malignant properties of epithelial-mesenchymal transition in cancer.
Isolating and targeting the real-time plasticity and malignant properties of epithelial-mesenchymal transition in cancer.
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DOI：
10.1038/s41388-021-01728-2
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发表时间：
2021-04
期刊：
影响因子：
8
通讯作者：
LaBarbera DV
中科院分区：
文献类型：
--
作者：
Esquer H;Zhou Q;Nemkov T;Abraham AD;Rinaldetti S;Chen YC;Zhang X;Orman MV;D'Alessandro A;Ferrer M;Messersmith WA;LaBarbera DV
上皮-间质转化（EMT）是促进恶性肿瘤发生、生长和转移的驱动力。EMT是一个动态过程，可以经历间充质-上皮转化（MET）和两种表型之间的部分转化，称为上皮-间充质可塑性（EMP）。在癌症中，EMP的获得导致一系列表型，促进肿瘤细胞异质性和对标准治疗的抗性。在这里，我们描述了一个实时荧光双报告波形蛋白和E-钙粘蛋白，间充质和上皮细胞表型的生物标志物，分别。从结直肠癌（SW 620）、肺癌（A549）和乳腺癌（MDA-MB-231）产生的稳定的双报告细胞系证明了一系列EMT细胞表型。我们使用双报告基因来分离准上皮、上皮/间充质和间充质表型。虽然EMT是一个动态的过程，这些孤立的准EMT表型保持稳定的自发EMP在没有刺激和长期的细胞培养。然而，准EMT表型可以容易地被诱导经历EMT或MET与生长因子或小分子。此外，孤立的EMT表型显示出不同的致瘤特性，并且在形态学和代谢上是不同的。使用双报告间充质SW 620肿瘤类器官对约23，000种化合物进行了3D高含量筛选，确定了调节EMT的小分子探针和有效诱导MET的探针子集。本文所述的工具、探针和模型提供了对间充质细胞可塑性的连贯的机制理解。利用这种技术和探针的未来应用有望促进我们对EMT的理解和针对EMT的治疗策略的研究。
Epithelial-mesenchymal transition (EMT) is a driving force in promoting malignant cancer, including initiation, growth, and metastasis. EMT is a dynamic process that can undergo a mesenchymal-epithelial transition (MET) and partial transitions between both phenotypes, termed epithelial-mesenchymal plasticity (EMP). In cancer, the acquisition of EMP results in a spectrum of phenotypes, promoting tumor cell heterogeneity and resistance to standard of care therapy. Here we describe a real-time fluorescent dual-reporter for vimentin and E-cadherin, biomarkers of the mesenchymal and epithelial cell phenotypes, respectively. Stable dual-reporter cell lines generated from colorectal (SW620), lung (A549), and breast (MDA-MB-231) cancer demonstrate a spectrum of EMT cell phenotypes. We used the dual-reporter to isolate the quasi epithelial, epithelial/mesenchymal, and mesenchymal phenotypes. Although EMT is a dynamic process, these isolated quasi-EMT-phenotypes remain stable to spontaneous EMP in the absence of stimuli and during prolonged cell culture. However, the quasi-EMT phenotypes can readily be induced to undergo EMT or MET with growth factors or small molecules. Moreover, isolated EMT phenotypes display different tumorigenic properties and are morphologically and metabolically distinct. 3D high-content screening of ~23,000 compounds using dual-reporter mesenchymal SW620 tumor organoids identified small molecule probes that modulate EMT, and a subset of probes that effectively induced MET. The tools, probes, and models described herein provide a coherent mechanistic understanding of mesenchymal cell plasticity. Future applications utilizing this technology and probes are expected to advance our understanding of EMT and studies aimed at therapeutic strategies targeting EMT.
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影响因子：
--
作者：
Clasquin, Michelle F;Melamud, Eugene;Rabinowitz, Joshua D
通讯作者：
Rabinowitz, Joshua D
影响因子：
3.1
作者：
Esquer, Hector;Zhou, Qiong;LaBarbera, Daniel V.
通讯作者：
LaBarbera, Daniel V.
影响因子：
2.5
作者：
Leggett, Susan E.;Sim, Jea Yun;Wong, Ian Y.
通讯作者：
Wong, Ian Y.
影响因子：
64.5
作者：
Faubert B;Li KY;Cai L;Hensley CT;Kim J;Zacharias LG;Yang C;Do QN;Doucette S;Burguete D;Li H;Huet G;Yuan Q;Wigal T;Butt Y;Ni M;Torrealba J;Oliver D;Lenkinski RE;Malloy CR;Wachsmann JW;Young JD;Kernstine K;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
5
作者：
Ackland, ML;Newgreen, DF;Thompson, EW
通讯作者：
Thompson, EW