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

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, Darren Ennis, Hala Ali, Fernanda G. Kugeratski, Heba Al Khamici, Maartje van den Biggelaar, Peter V.E. van den Berghe, Catherine Cloix, Laura McDonald, David Millan, Aoisha Hoyle, Anna Kuchnio, Peter Carmeliet, Stella M. Valenzuela, Karen Blyth, Huabing Yin, Massimiliano Mazzone, Jim C. Norman () and Sara Zanivan ()
Additional contact information
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
Fernanda G. Kugeratski: Cancer Research UK Beatson Institute
Heba Al Khamici: School of Life Sciences, 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
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

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14206

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