期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms14909
关键词
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资金
- CRUK Manchester Institute [C5759/A12328]
- Division of Cancer Therapeutics at The Institute of Cancer Research [C309/A11566]
- Wellcome Trust [1003X, 103021/Z/13/Z, 100282/Z/12/Z]
- Wellcome Trust [103021/Z/13/Z] Funding Source: Wellcome Trust
- Cancer Research UK [22902, 11566] Funding Source: researchfish
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 TGF beta 1 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.
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