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, Richard Marais

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)14909
Number of pages1
JournalNature Communications
Volume8
Early online date18 Apr 2017
DOIs
Publication statusPublished - Apr 2017

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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