Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. Author Toni Celià-Terrassa, Caleb Bastian, Daniel Liu, Brian Ell, Nicole Aiello, Yong Wei, Jose Zamalloa, Andres Blanco, Xiang Hang, Dmitriy Kunisky, Wenyang Li, Elizabeth Williams, Herschel Rabitz, Yibin Kang Publication Year 2018 Type Journal Article 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. Keywords Animals, Models, Biological, Feedback, Physiological, MicroRNAs, Female, Cell Line, Tumor, Epithelial Cells, Cadherins, Epithelial-Mesenchymal Transition, Mice, Inbred BALB C, Neoplasm Metastasis, Transforming Growth Factor beta, Zinc Finger E-box-Binding Homeobox 1 Journal Nat Commun Volume 9 Issue 1 Pages 5005 Date Published 2018 Nov 27 ISSN Number 2041-1723 DOI 10.1038/s41467-018-07538-7 Alternate Journal Nat Commun PMCID PMC6258667 PMID 30479345 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML