Title | Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Celià-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 |
Journal | Nat Commun |
Volume | 9 |
Issue | 1 |
Pagination | 5005 |
Date Published | 2018 Nov 27 |
ISSN | 2041-1723 |
Keywords | Animals, 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 | <p>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.</p> |
DOI | 10.1038/s41467-018-07538-7 |
Alternate Journal | Nat Commun |
PubMed ID | 30479345 |
PubMed Central ID | PMC6258667 |
Grant List | K08 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 |