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dc.contributor.authorTang, Haoran
dc.contributor.authorLeung, L
dc.contributor.authorSaturno, Grazia
dc.contributor.authorViros, Amaya
dc.contributor.authorSmith, Duncan L
dc.contributor.authorDi Leva, Gianpiero
dc.contributor.authorMorrison, Eamonn
dc.contributor.authorNiculescu-Duvaz, D
dc.contributor.authorLopes, F
dc.contributor.authorJohnson, L
dc.contributor.authorDhomen, Nathalie
dc.contributor.authorSpringer, Caroline
dc.contributor.authorMarais, Richard
dc.date.accessioned2017-05-12T12:22:44Z
dc.date.available2017-05-12T12:22:44Z
dc.date.issued2017-04-18
dc.identifier.citationLysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface. 2017, 8:14909 Nat Communen
dc.identifier.issn2041-1723
dc.identifier.pmid28416796
dc.identifier.doi10.1038/ncomms14909
dc.identifier.urihttp://hdl.handle.net/10541/620354
dc.description.abstractLysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo. Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623.
dc.language.isoenen
dc.rightsArchived with thanks to Nature communicationsen
dc.titleLysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.en
dc.typeArticleen
dc.contributor.departmentMolecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BXen
dc.identifier.journalNature Communicationsen
refterms.dateFOA2018-12-17T14:55:14Z
html.description.abstractLysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo. Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623.


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