Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 45, Pages 18144-18149Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1318192110
Keywords
multistable decision circuit; partial EMT; cancer systems biology; microRNA modeling; metastable intermediate phenotypes
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Funding
- National Science Foundation NSF) Center for Theoretical Biological Physics Grant [NSF PHY-1308264]
- Cancer Prevention and Research Institute of Texas (CPRIT) Scholar Program of the State of Texas at Rice University
- Tauber Family Funds at Tel-Aviv University
- Division Of Physics
- Direct For Mathematical & Physical Scien [1308264] Funding Source: National Science Foundation
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Forward and backward transitions between epithelial and mesenchymal phenotypes play crucial roles in embryonic development and tissue repair. Aberrantly regulated transitions are also a hallmark of cancer metastasis. The genetic network that regulates these transitions appears to allow for the existence of a hybrid phenotype (epithelial/mesenchymal). Hybrid cells are endowed with mixed epithelial and mesenchymal characteristics, enabling specialized capabilities such as collective cell migration. Cell-fate determination between the three phenotypes is in fact regulated by a circuit composed of two highly interconnected chimeric modules- the miR-34/SNAIL and the miR-200/ZEB mutual-inhibition feedback circuits. Here, we used detailed modeling of microRNAbased regulation to study this core unit. More specifically, we investigated the functions of the two isolated modules and subsequently of the combined unit when the two modules are integrated into the full regulatory circuit. We found that miR-200/ZEB forms a tristable circuit that acts as a ternary switch, driven by miR-34/ SNAIL, that is a monostable module that acts as a noise-buffering integrator of internal and external signals. We propose to associate the three stable states-(1,0), (high miR-200)/(low ZEB); (0,1), (low miR-200)/(high ZEB); and (1/2,1/2), (medium miR-200)/(medium ZEB)with the epithelial, mesenchymal, and hybrid phenotypes, respectively. Our (1/2,1/2) state hypothesis is consistent with recent experimental studies (e.g., ZEB expressionmeasurements in collectively migrating cells) and explains the lack of observed mesenchymalto- hybrid transitions in metastatic cells and in induced pluripotent stem cells. Testable predictions of dynamic gene expression during complete and partial transitions are presented.
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