Journal
SCIENTIFIC REPORTS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep17379
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Funding
- NSF Center for Theoretical Biological Physics [PHY-1427654]
- Cancer Prevention and Research Institute of Texas (CPRIT)
- Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (CPRIT Grant) [RP140113]
- Tauber Family Funds
- Maguy-Glass Chair in Physics of Complex Systems
- Breast Cancer Research Foundation
- United States-Israel Binational Science Foundation
- Federico Foundation Grants
- Division Of Physics
- Direct For Mathematical & Physical Scien [1427654] Funding Source: National Science Foundation
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Cellular plasticity during cancer metastasis is a major clinical challenge. Two key cellular plasticity mechanisms -Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Amoeboid Transition (MAT) - have been carefully investigated individually, yet a comprehensive understanding of their interconnections remains elusive. Previously, we have modeled the dynamics of the core regulatory circuits for both EMT (miR-200/ZEB/miR-34/SNAIL) and MAT (Rac1/RhoA). We now extend our previous work to study the coupling between these two core circuits by considering the two microRNAs (miR-200 and miR-34) as external signals to the core MAT circuit. We show that this coupled circuit enables four different stable steady states (phenotypes) that correspond to hybrid epithelial/mesenchymal (E/M), mesenchymal (M), amoeboid (A) and hybrid amoeboid/mesenchymal (A/M) phenotypes. Our model recapitulates the metastasis-suppressing role of the microRNAs even in the presence of EMT-inducing signals like Hepatocyte Growth Factor (HGF). It also enables mapping the microRNA levels to the transitions among various cell migration phenotypes. Finally, it offers a mechanistic understanding for the observed phenotypic transitions among different cell migration phenotypes, specifically the Collective-to-Amoeboid Transition (CAT).
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