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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition* / drug effects
  • Feedback, Physiological
  • Female
  • Mice, Inbred BALB C
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Models, Biological
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology*
  • Transforming Growth Factor beta / pharmacology
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism

Substances

  • Cadherins
  • MIRN200 microRNA, human
  • MicroRNAs
  • Transforming Growth Factor beta
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1