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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 , 2017. "Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14909
    DOI: 10.1038/ncomms14909
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    Cited by:

    1. Jing Bi & Zhihui Wu & Xin Zhang & Taoling Zeng & Wanjun Dai & Ningyuan Qiu & Mingfeng Xu & Yikai Qiao & Lang Ke & Jiayi Zhao & Xinyu Cao & Qi Lin & Xiao Lei Chen & Liping Xie & Zhong Ouyang & Jujiang , 2023. "TMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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