Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms14206
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Funding
- Cancer Research U.K. [C596/A17196, C596/A12935, C596/A18277]
- Breast Cancer Now Pilot Grants [SP001, SP442]
- Federal Government Belgium grant [IUAP P7/03]
- Flemish Government
- Research Foundation Flanders (FWO)
- Foundation against cancer
- European Research Council (ERC) Advanced Research Grant [EU-ERC269073]
- AXA Research Fund
- MRC [MR/P01058X/1, G0501974] Funding Source: UKRI
- Cancer Research UK [19257, 22311, 18277, 12935, 29800] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [1522354] Funding Source: researchfish
- Medical Research Council [G0501974, MR/P01058X/1] Funding Source: researchfish
- Ovarian Cancer Action [OCA6] Funding Source: researchfish
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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.
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