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

Toni Celià-Terrassa, Caleb Bastian, Daniel Liu, Brian Ell, Nicole M. Aiello, Yong Wei, Jose Zamalloa, Andres M. Blanco, Xiang Hang, Dmitriy Kunisky, Wenyang Li, Elizabeth D. Williams, Herschel Rabitz, Yibin Kang

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31 Scopus citations

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.

Original languageEnglish (US)
Article number5005
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Celià-Terrassa, T., Bastian, C., Liu, D., Ell, B., Aiello, N. M., Wei, Y., Zamalloa, J., Blanco, A. M., Hang, X., Kunisky, D., Li, W., Williams, E. D., Rabitz, H., & Kang, Y. (2018). Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. Nature communications, 9(1), [5005]. https://doi.org/10.1038/s41467-018-07538-7