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上皮-间充质转化动力学的滞后控制传递出一个具有增强转移能力的独特程序。

Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability.

机构信息

Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.

Cancer Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, 08003, Spain.

出版信息

Nat Commun. 2018 Nov 27;9(1):5005. doi: 10.1038/s41467-018-07538-7.

DOI:10.1038/s41467-018-07538-7
PMID:30479345
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6258667/
Abstract

Epithelial-mesenchymal transition (EMT) have been extensively characterized in development and cancer, and its dynamics have been modeled as a non-linear process. However, less is known about how such dynamics may affect its biological impact. Here, we use mathematical modeling and experimental analysis of the TGF-β-induced EMT to reveal a non-linear hysteretic response of E-cadherin repression tightly controlled by the strength of the miR-200s/ZEBs negative feedback loop. Hysteretic EMT conveys memory state, ensures rapid and robust cellular response and enables EMT to persist long after withdrawal of stimuli. Importantly, while both hysteretic and non-hysteretic EMT confer similar morphological changes and invasive potential of cancer cells, only hysteretic EMT enhances lung metastatic colonization efficiency. Cells that undergo hysteretic EMT differentially express subsets of stem cell and extracellular matrix related genes with significant clinical prognosis value. These findings illustrate distinct biological impact of EMT depending on the dynamics of the transition.

摘要

上皮-间充质转化 (EMT) 在发育和癌症中得到了广泛的研究，其动力学已被建模为非线性过程。然而，对于这种动力学如何影响其生物学影响知之甚少。在这里，我们使用数学建模和 TGF-β 诱导的 EMT 的实验分析，揭示了 miR-200s/ZEBs 负反馈环的强度对 E-钙黏蛋白抑制的非线性滞后反应的紧密控制。滞后 EMT 传递记忆状态，确保快速和强大的细胞反应，并使 EMT 在刺激物撤出后长时间持续。重要的是，虽然滞后 EMT 和非滞后 EMT 赋予癌细胞相似的形态变化和侵袭潜能，但只有滞后 EMT 增强了肺癌转移定植的效率。经历滞后 EMT 的细胞差异表达与干细胞和细胞外基质相关基因的子集，具有显著的临床预后价值。这些发现说明了 EMT 的不同生物学影响取决于转变的动力学。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/62ec4c744f8d/41467_2018_7538_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/24e1c668f15a/41467_2018_7538_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/6d236186b463/41467_2018_7538_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/cee33979f061/41467_2018_7538_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/5496c260a15e/41467_2018_7538_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/62ec4c744f8d/41467_2018_7538_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/24e1c668f15a/41467_2018_7538_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/6d236186b463/41467_2018_7538_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/cee33979f061/41467_2018_7538_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/5496c260a15e/41467_2018_7538_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/06db/6258667/62ec4c744f8d/41467_2018_7538_Fig5_HTML.jpg

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