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

TitleHysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability.
Publication TypeJournal Article
Year of Publication2018
AuthorsCelià-Terrassa, T, Bastian, C, Liu, DD, Ell, B, Aiello, NM, Wei, Y, Zamalloa, J, Blanco, AM, Hang, X, Kunisky, D, Li, W, Williams, ED, Rabitz, H, Kang, Y
JournalNat Commun
Volume9
Issue1
Pagination5005
Date Published2018 11 27
ISSN2041-1723
KeywordsAnimals, Cadherins, Cell Line, Tumor, Epithelial Cells, Epithelial-Mesenchymal Transition, Feedback, Physiological, Female, Mice, Inbred BALB C, MicroRNAs, Models, Biological, Neoplasm Metastasis, Transforming Growth Factor beta, Zinc Finger E-box-Binding Homeobox 1
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.

DOI10.1038/s41467-018-07538-7
Alternate JournalNat Commun
PubMed ID30479345
PubMed Central IDPMC6258667
Grant ListK08 DE021430 / DE / NIDCR NIH HHS / United States
P30 CA072720 / CA / NCI NIH HHS / United States
R01 CA141062 / CA / NCI NIH HHS / United States
R01 CA198280 / CA / NCI NIH HHS / United States