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Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.

Tang, HaoRan; Leung, Leo; Saturno, Grazia; Viros, Amaya; Smith, Duncan; Di Leva, Gianpiero; Morrison, Eamonn; Niculescu-Duvaz, Dan; Lopes, Filipa; Johnson, Louise; Dhomen, Nathalie; Springer, Caroline; Marais, Richard

Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface. Thumbnail


Authors

HaoRan Tang

Leo Leung

Grazia Saturno

Amaya Viros

Duncan Smith

Eamonn Morrison

Dan Niculescu-Duvaz

Filipa Lopes

Louise Johnson

Nathalie Dhomen

Caroline Springer

Richard Marais



Abstract

Lysyl 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 TGFß1 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.

Journal Article Type Article
Acceptance Date Feb 9, 2017
Publication Date Apr 18, 2017
Publicly Available Date Mar 28, 2024
Journal Nature Communications
Print ISSN 2041-1723
Peer Reviewed Peer Reviewed
Volume 8
Article Number 14909
DOI https://doi.org/10.1038/ncomms14909
Keywords cancer microenvironment, extracellular signalling molecules, Aminopropionitrile, Animals, Biosensing Techniques, Cell Line, Tumor, Cell Membrane, Cell Proliferation, Disease Progression, Dogs, Enzyme Activation, Enzyme Inhibitors, Epidermal Growth Factor,
Publisher URL https://doi.org/10.1038/ncomms14909

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