Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.
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Embargo End Date
ICR Authors
Authors
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
Marais, R
Leung, L
Saturno, G
Viros, A
Smith, D
Di Leva, G
Morrison, E
Niculescu-Duvaz, D
Lopes, F
Johnson, L
Dhomen, N
Springer, C
Marais, R
Document Type
Journal Article
Date
2017-04-18
Date Accepted
2017-02-09
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.
Citation
Nature communications, 2017, 8 pp. 14909 - ?
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Gene & Oncogene Targeting