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

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.

Citation

Tang, H., Leung, L., Saturno, G., Viros, A., Smith, D., Di Leva, G., …Marais, R. (2017). Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface. Nature communications, 8, Article 14909. https://doi.org/10.1038/ncomms14909

• Journal Article Type: Article
• Acceptance Date: Feb 9, 2017
• Publication Date: Apr 18, 2017
• 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