Tang, H, Leung, L, Saturno, G, Viros, A, Smith, D, Di Leva, G, Morrison, E, Niculescu-Duvaz, D, Lopes, F, Johnson, L, Dhomen, N, Springer, C and Marais, R (2017) Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface. Nature Communications, 8. 14909 -?.

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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 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.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via Nature Research at https://doi.org/10.1038/ncomms14909 - please refer to any applicable terms of use of the publisher.
Uncontrolled 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, ErbB Receptors, High-Temperature Requirement A Serine, Peptidase 1, Humans, Matrilin Proteins, Mice, Models, Biological, Neoplasm, Metastasis, Neoplasms, Protein-Lysine 6-Oxidase, Rats, Signal Transduction, Transforming Growth Factor beta1
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
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Depositing User: Symplectic
Date Deposited: 26 Apr 2019 13:11
Last Modified: 26 Apr 2019 13:20
URI: http://eprints.keele.ac.uk/id/eprint/6214

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