title: Modeling the Transitions between Collective and Solitary Migration Phenotypes in Cancer Metastasis.
abstract: 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).
authors.affiliation: Center for Theoretical Biological Physics, Houston, TX 77005-1827, USA.|Department of Chemistry, Houston, TX 77005-1827, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Center for Theoretical Biological Physics, Houston, TX 77005-1827, USA.|Department of Bioengineering, Houston, TX 77005-1827, USA.
authors.forename: Mohit Kumar
authors.initials: MK
authors.lastname: Jolly
authors.affiliation: Center for Theoretical Biological Physics, Houston, TX 77005-1827, USA.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Tsarfaty
authors.affiliation: Center for Theoretical Biological Physics, Houston, TX 77005-1827, USA.|Department of Biosciences, Rice University, Houston, TX 77005-1827, USA.|School of Physics and Astronomy and The Sagol School of Neuroscience Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Eshel
authors.initials: E
authors.lastname: Ben-Jacob
authors.affiliation: Center for Theoretical Biological Physics, Houston, TX 77005-1827, USA.|Department of Chemistry, Houston, TX 77005-1827, USA.|Department of Physics and Astronomy, Houston, TX 77005-1827, USA.|Department of Biosciences, Rice University, Houston, TX 77005-1827, USA.
authors.forename: Jose' N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D000818:Animals; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism
chemical_list: C533896:MIRN200 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm