CLIC3 controls recycling of late endosomal MT1-MMP and dictates invasion and metastasis in breast cancer

MacPherson, I. R. et al. (2014) CLIC3 controls recycling of late endosomal MT1-MMP and dictates invasion and metastasis in breast cancer. Journal of Cell Science, 127(18), pp. 3893-3901. (doi: 10.1242/jcs.135947) (PMID:25015290)

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Chloride intracellular channel 3 (CLIC3) drives invasiveness of pancreatic and ovarian cancer by acting in concert with Rab25 to regulate the recycling of α5β1 integrin from late endosomes to the plasma membrane. Here, we show that in two estrogen receptor (ER)-negative breast cancer cell lines, CLIC3 has little influence on integrin recycling, but controls trafficking of the pro-invasive matrix metalloproteinase MT1-MMP (also known as MMP14). In MDA-MB-231 cells, MT1-MMP and CLIC3 are localized primarily to late endosomal/lysosomal compartments located above the plane of adhesion and near the nucleus. MT1-MMP is transferred from these late endosomes to sites of cell–matrix adhesion in a CLIC3-dependent fashion. Correspondingly, CLIC3-knockdown opposes MT1-MMP-dependent invasive processes. These include the disruption of the basement membrane as acini formed from cells acquire invasive characteristics in 3D culture, and the invasion of MDA-MB-231 cells into Matrigel or organotypic plugs of type I collagen. Consistent with this, expression of CLIC3 predicts poor prognosis in ER-negative breast cancer. The identification of MT1-MMP as a cargo of a CLIC3-regulated pathway that drives invasion highlights the importance of late endosomal sorting and trafficking in breast cancer.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Rainero, Ms Elena and Kalna, Dr Gabriela and Edwards, Professor Joanne and Timpson, Dr Paul and Speirs, Miss Claire and Van Den Berghe, Dr Peter and MacPherson, Professor Iain and Norman, Professor James and Mitchell, Mrs Louise
Authors: MacPherson, I. R., Rainero, E., Mitchell, L. E., van den Berghe, P. V.E., Speirs, C., Dozynkiewicz, M. A., Chaudhary, S., Kalna, G., Edwards, J., Timpson, P., and Norman, J. C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of Cell Science
Publisher:Company of Biologists Ltd.
ISSN (Online):0021-9533
Published Online:11 July 2014

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