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

HaoRan Tang, Leo Leung, Grazia Saturno, Amaya Viros, Duncan Smith, Gianpiero Di Leva, Eamonn Morrison, Dan Niculescu-Duvaz, Filipa Lopes, Louise Johnson, Nathalie Dhomen, Caroline Springer () and Richard Marais ()
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HaoRan Tang: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester
Leo Leung: Gene and Oncogene Targeting Team, CRUK Cancer Therapeutics Unit, The Institute of Cancer Research
Grazia Saturno: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester
Amaya Viros: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester
Duncan Smith: Biological Mass Spectrometry Unit, Cancer Research UK Manchester Institute, University of Manchester
Gianpiero Di Leva: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester
Eamonn Morrison: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester
Dan Niculescu-Duvaz: Gene and Oncogene Targeting Team, CRUK Cancer Therapeutics Unit, The Institute of Cancer Research
Filipa Lopes: Gene and Oncogene Targeting Team, CRUK Cancer Therapeutics Unit, The Institute of Cancer Research
Louise Johnson: Gene and Oncogene Targeting Team, CRUK Cancer Therapeutics Unit, The Institute of Cancer Research
Nathalie Dhomen: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester
Caroline Springer: Gene and Oncogene Targeting Team, CRUK Cancer Therapeutics Unit, The Institute of Cancer Research
Richard Marais: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14909

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