title: Toward decoding the principles of cancer metastasis circuits.
abstract: Understanding epithelial-mesenchymal transitions (EMT) during cancer metastasis remains a major challenge in modern biology. Recent observations of cell behavior together with progress in mapping the underlying regulatory genetic networks led to new understandings of carcinoma metastasis. It is now established that the genetic network that regulates the EMT also enables an epithelial-mesenchymal hybrid phenotype. These hybrid cells possess mixed carcinoma epithelial and mesenchymal characteristics that enable specialized capabilities such as collective cell migration. On the gene network perspective, a four-component decision unit composed of two highly interconnected chimeric modules--the miR34/SNAIL and the miR200/ZEB mutual-inhibition feedback circuits--regulates the coexistence of and transitions between the different phenotypes. Here, we present a new tractable theoretical framework to model and decode the underlying principles governing the operation of the regulatory unit. Our approach connects the knowledge about intracellular pathways with observations of cellular behavior and advances toward understanding the logic of cancer decision-making. We found that the miR34/SNAIL module acts as an integrator while the miR200/ZEB module acts as a three-way switch. Consequently, the combined unit can give rise to three phenotypes (stable states): (i) a high miR200 and low ZEB, or (1, 0) state; (ii) a low miR200 and high ZEB, or (0, 1) state; and (iii) a medium miR200 and medium ZEB, or (½, ½) state. We associate these states with the epithelial, mesenchymal, and hybrid phenotypes, respectively. We reflect on the consistency between our theoretical predictions and recent observations in several types of carcinomas and suggest new testable predictions. See all articles in this Cancer Research section,
authors.affiliation: Center for Theoretical Biological Physics, Departments of.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Lu
authors.affiliation: Center for Theoretical Biological Physics, Departments of Bioengineering.
authors.forename: Mohit Kumar
authors.initials: MK
authors.lastname: Jolly
authors.affiliation: Center for Theoretical Biological Physics, Departments of Physics and Astronomy, Chemistry, and Biochemistry and Cell Biology, Rice University, Houston, Texas; eshel@rice.edu jonuchic@rice.edu.
authors.forename: Jose'
authors.initials: J
authors.lastname: Onuchic
authors.affiliation: Center for Theoretical Biological Physics, Departments of Biochemistry and Cell Biology, Rice University, Houston, Texas; School of Physics and Astronomy; and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel eshel@rice.edu jonuchic@rice.edu.
authors.forename: Eshel
authors.initials: E
authors.lastname: Ben-Jacob
mesh_terms: D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1