title: Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity.
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.
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Hernandez-Fernaud
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Ruengeler
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Andrea
authors.initials: A
authors.lastname: Casazza
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Neilson
authors.affiliation: Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow G12 8LT, UK.
authors.forename: Ellie
authors.initials: E
authors.lastname: Pulleine
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Santi
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Shehab
authors.initials: S
authors.lastname: Ismail
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lilla
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dhayade
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G611QH, UK.
authors.forename: Iain R
authors.initials: IR
authors.lastname: MacPherson
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G611QH, UK.
authors.forename: Iain
authors.identifier: 0000-0002-9387-7586
authors.initials: I
authors.lastname: McNeish
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G611QH, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Ennis
authors.affiliation: School of Life Sciences, University of Technology Sydney, Sydney, New South Wales 2007, Australia.|Centre for Health Technologies, University of Technology Sydney, Sydney, New South Wales 2007, Australia.
authors.forename: Hala
authors.initials: H
authors.lastname: Ali
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Fernanda G
authors.initials: FG
authors.lastname: Kugeratski
authors.affiliation: School of Life Sciences, University of Technology Sydney, Sydney, New South Wales 2007, Australia.|Centre for Health Technologies, University of Technology Sydney, Sydney, New South Wales 2007, Australia.
authors.forename: Heba
authors.initials: H
authors.lastname: Al Khamici
authors.affiliation: Department of Plasma Proteins, Sanquin Research, Amsterdam 1066 CX, The Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: van den Biggelaar
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Peter V E
authors.initials: PV
authors.lastname: van den Berghe
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cloix
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: McDonald
authors.affiliation: Department of Pathology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
authors.forename: David
authors.initials: D
authors.lastname: Millan
authors.affiliation: Department of Pathology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
authors.forename: Aoisha
authors.initials: A
authors.lastname: Hoyle
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, Vesalius Research Center, VIB, B-3000 Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuchnio
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, Vesalius Research Center, VIB, B-3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: School of Life Sciences, University of Technology Sydney, Sydney, New South Wales 2007, Australia.|Centre for Health Technologies, University of Technology Sydney, Sydney, New South Wales 2007, Australia.
authors.forename: Stella M
authors.identifier: 0000-0001-5934-6047
authors.initials: SM
authors.lastname: Valenzuela
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
authors.affiliation: Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow G12 8LT, UK.
authors.forename: Huabing
authors.initials: H
authors.lastname: Yin
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Zanivan
mesh_terms: D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018118:Chloride Channels / Q000378:metabolism*; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010088:Oxidoreductases / Q000378:metabolism; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D016019:Survival Analysis; D011503:Transglutaminases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C117019:CLIC3 protein, human; D018118:Chloride Channels; D020543:Proteome; C000717608:TGM2 protein, human; D010088:Oxidoreductases; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D005978:Glutathione