Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.
Date
2017-04-18ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
Cell Membrane
Animals
Dogs
Humans
Mice
Rats
Neoplasms
Neoplasm Metastasis
Disease Progression
Aminopropionitrile
Epidermal Growth Factor
Protein-Lysine 6-Oxidase
Enzyme Inhibitors
Biosensing Techniques
Signal Transduction
Cell Proliferation
Enzyme Activation
Models, Biological
Transforming Growth Factor beta1
Matrilin Proteins
ErbB Receptors
High-Temperature Requirement A Serine Peptidase 1
Research team
Gene & Oncogene Targeting
Language
eng
Date accepted
2017-02-09
License start date
2017-04-18
Citation
Nature communications, 2017, 8 pp. 14909 - ?
Publisher
NATURE PUBLISHING GROUP