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Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity

Author

Listed:
  • Juan R. Hernandez-Fernaud

    (Cancer Research UK Beatson Institute)

  • Elena Ruengeler

    (Cancer Research UK Beatson Institute)

  • Andrea Casazza

    (Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB)

  • Lisa J. Neilson

    (Cancer Research UK Beatson Institute)

  • Ellie Pulleine

    (School of Engineering, University of Glasgow)

  • Alice Santi

    (Cancer Research UK Beatson Institute)

  • Shehab Ismail

    (Cancer Research UK Beatson Institute)

  • Sergio Lilla

    (Cancer Research UK Beatson Institute)

  • Sandeep Dhayade

    (Cancer Research UK Beatson Institute)

  • Iain R. MacPherson

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow)

  • Iain McNeish

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow)

  • Darren Ennis

    (Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow)

  • Hala Ali

    (School of Life Sciences, University of Technology Sydney
    Centre for Health Technologies, University of Technology Sydney)

  • Fernanda G. Kugeratski

    (Cancer Research UK Beatson Institute)

  • Heba Al Khamici

    (School of Life Sciences, University of Technology Sydney
    Centre for Health Technologies, University of Technology Sydney)

  • Maartje van den Biggelaar

    (Sanquin Research)

  • Peter V.E. van den Berghe

    (Cancer Research UK Beatson Institute)

  • Catherine Cloix

    (Cancer Research UK Beatson Institute)

  • Laura McDonald

    (Cancer Research UK Beatson Institute)

  • David Millan

    (Queen Elizabeth University Hospital)

  • Aoisha Hoyle

    (Queen Elizabeth University Hospital)

  • Anna Kuchnio

    (Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, Vesalius Research Center, VIB)

  • Peter Carmeliet

    (Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, Vesalius Research Center, VIB)

  • Stella M. Valenzuela

    (School of Life Sciences, University of Technology Sydney
    Centre for Health Technologies, University of Technology Sydney)

  • Karen Blyth

    (Cancer Research UK Beatson Institute)

  • Huabing Yin

    (School of Engineering, University of Glasgow)

  • Massimiliano Mazzone

    (Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB)

  • Jim C. Norman

    (Cancer Research UK Beatson Institute)

  • Sara Zanivan

    (Cancer Research UK Beatson Institute)

Abstract

The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion.

Suggested Citation

  • Juan R. Hernandez-Fernaud & Elena Ruengeler & Andrea Casazza & Lisa J. Neilson & Ellie Pulleine & Alice Santi & Shehab Ismail & Sergio Lilla & Sandeep Dhayade & Iain R. MacPherson & Iain McNeish & Dar, 2017. "Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity," Nature Communications, Nature, vol. 8(1), pages 1-17, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14206
    DOI: 10.1038/ncomms14206
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    Cited by:

    1. Amy Dawson & Martha M. Zarou & Bodhayan Prasad & Joana Bittencourt-Silvestre & Désirée Zerbst & Ekaterini Himonas & Ya-Ching Hsieh & Isabel Loon & Giovanny Rodriguez Blanco & Angela Ianniciello & Zsom, 2024. "Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Noemi Gioelli & Lisa J. Neilson & Na Wei & Giulia Villari & Wenqian Chen & Bernhard Kuhle & Manuel Ehling & Federica Maione & Sander Willox & Serena Brundu & Daniele Avanzato & Grigorios Koulouras & M, 2022. "Neuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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