title: Actinomyosin contraction, phosphorylation of VE-cadherin, and actin remodeling enable melanoma-induced endothelial cell-cell junction disassembly.
abstract: During melanoma cell extravasation through the vascular endothelium, melanoma cells interact with endothelial cells through secretion of cytokines and by adhesion between proteins displayed on opposing cell surfaces. How these tumor cell associated signals together regulate the dynamics of intracellular signaling pathways within endothelial cells leading to endothelial cell-cell junction disruption is not well understood. Here, we used a combination of experimental and computational approaches to examine the individual and combined effects of activation of the vascular cell adhesion molecule (VCAM)-1, interleukin (IL)-8, and IL-1β signaling pathways on the integrity of vascular junctions. Our simulations predict a multifaceted interplay of signaling resulting from individual activation of VCAM-1, IL-8 and IL-1β pathways that is neither synergistic nor additive compared to all inputs turned on simultaneously. Furthermore, we show that the levels of phosphorylated proteins associated with actinomyosin contractility and junction disassembly peak prior to those related to actin remodeling. The results of this work provide insight into the dynamics of tumor-mediated endothelial junction disassembly and suggest that targeting proteins downstream of several interaction pathways may be the most effective therapeutic approach to reduce melanoma extravasation.
authors.affiliation: Department of Biomedical Engineering, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Weidert
authors.affiliation: Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Pohler
authors.affiliation: Department of Biomedical Engineering, The Pennsylvania State University, University Park, Pennsylvania, United States of America; Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Esther W
authors.initials: EW
authors.lastname: Gomez
authors.affiliation: Department of Biomedical Engineering, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Cheng
authors.initials: C
authors.lastname: Dong
mesh_terms: D000199:Actins / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003599:Cytoskeleton / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D055786:Gene Knockout Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D053583:Interleukin-1beta; D016209:Interleukin-8; D009219:Myosin-Light-Chain Kinase; D019010:Vascular Cell Adhesion Molecule-1; D000099152:Cadherin 5