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

• Published in: Nature communications Vol. 8; no. 1; p. 14909
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.04.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/10; 631/67/327; 631/80/86/820; 82; 82/51; 96; 96/35; Aminopropionitrile - chemistry; Aminopropionitrile - pharmacology; Animals; Biosensing Techniques; Breast cancer; Cancer research; Cell Line, Tumor; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Proliferation - drug effects; Cells; Collagen; Disease Progression; Dogs; Enzyme Activation; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Epidermal growth factor; Epidermal Growth Factor - pharmacology; ErbB Receptors - metabolism; Extracellular matrix; High-Temperature Requirement A Serine Peptidase 1 - metabolism; Humanities and Social Sciences; Humans; Kinases; Matrilin Proteins - metabolism; Medical research; Metastasis; Mice; Models, Biological; multidisciplinary; Neoplasm Metastasis; Neoplasms - metabolism; Neoplasms - pathology; Phosphorylation; Protein-Lysine 6-Oxidase - antagonists & inhibitors; Protein-Lysine 6-Oxidase - metabolism; Proteins; Rats; Retention; Science; Signal Transduction - drug effects; Transforming Growth Factor beta1 - metabolism; United Kingdom > UK
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14909

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 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. Lysyl oxidase is able to remodel the extracellular matrix and its expression correlates with poor prognosis. Here the authors show that this protein modulates trapping of the epidermal growth factor receptor at the cell surface, causing persistent signalling activation and tumour progression.