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    Phosphoproteomic analysis of interacting tumor and endothelial cells identifies regulatory mechanisms of transendothelial migration.

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    Authors
    Locard-Paulet, Marie
    Lim, L
    Veluscek, Giulia
    McMahon, Kelly M
    Sinclair, J
    van Weverwijk, A
    Worboys, Jonathan D
    Yuan, Y
    Isacke, C
    Jørgensen, Claus
    Affiliation
    Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London
    Issue Date
    2016
    
    Metadata
    Show full item record
    Abstract
    The exit of metastasizing tumor cells from the vasculature, extravasation, is regulated by their dynamic interactions with the endothelial cells that line the internal surface of vessels. To elucidate signals controlling tumor cell adhesion to the endothelium and subsequent transendothelial migration, we performed phosphoproteomic analysis to map cell-specific changes in protein phosphorylation that were triggered by contact between metastatic MDA-MB-231 breast cancer cells and endothelial cells. From the 2669 unique phosphorylation sites identified, 77 and 43 were differentially phosphorylated in the tumor cells and endothelial cells, respectively. The receptor tyrosine kinase ephrin type A receptor 2 (EPHA2) exhibited decreased Tyr(772) phosphorylation in the cancer cells upon endothelial contact. Knockdown of EPHA2 increased adhesion of the breast cancer cells to human umbilical vein endothelial cells (HUVECs) and their transendothelial migration in coculture cell assays, as well as early-stage lung colonization in vivo. EPHA2-mediated inhibition of transendothelial migration of breast cancer cells depended on interaction with the ligand ephrinA1 on HUVECs and phosphorylation of EPHA2-Tyr(772). When EPHA2 phosphorylation dynamics were compared between cell lines of different metastatic ability, EPHA2-Tyr(772) was rapidly dephosphorylated after ephrinA1 stimulation specifically in cells targeting the lung. Knockdown of the phosphatase LMW-PTP reduced adhesion and transendothelial migration of the breast cancer cells. Overall, cell-specific phosphoproteomic analysis provides a bidirectional map of contact-initiated signaling between tumor and endothelial cells that can be further investigated to identify mechanisms controlling the transendothelial cell migration of cancer cells.
    Citation
    Phosphoproteomic analysis of interacting tumor and endothelial cells identifies regulatory mechanisms of transendothelial migration. 2016, 9 (414):ra15 Sci Signal
    Journal
    Science Signaling
    URI
    http://hdl.handle.net/10541/600562
    DOI
    10.1126/scisignal.aac5820
    PubMed ID
    26861043
    Type
    Article
    Language
    en
    ISSN
    1937-9145
    ae974a485f413a2113503eed53cd6c53
    10.1126/scisignal.aac5820
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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