Catalytically inactive human cathepsin D triggers fibroblast invasive growth

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Abstract

The aspartyl-protease cathepsin D (cath-D) is over-expressed and hypersecreted by epithelial breast cancer cells and stimulates their proliferation. As tumor epithelial-fibroblast cell interactions are important events in cancer progression, we investigated whether cath-D overexpression affects also fibroblast behavior. We demonstrate a requirement of cath-D for fibroblast invasive growth using a three-dimensional (3D) coculture assay with cancer cells secreting or not pro-cath-D. Ectopic expression of cath-D in cath-D-deficient fibroblasts stimulates 3D outgrowth that is associated with a significant increase in fibroblast proliferation, survival, motility, and invasive capacity, accompanied by activation of the rasMAPK pathway. Interestingly, all these stimulatory effects on fibroblasts are independent of cath-D proteolytic activity. Finally, we show that pro-cath-D secreted by cancer cells is captured by fibroblasts and partially mimics effects of transfected cath-D. We conclude that cath-D is crucial for fibroblast invasive outgrowth and could act as a key paracrine communicator between cancer and stromal cells, independently of its catalytic activity.

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Laurent-Matha, V., Maruani-Herrmann, S., Prébois, C., Beaujouin, M., Glondu, M., Noël, A., … Liaudet-Coopman, E. (2005). Catalytically inactive human cathepsin D triggers fibroblast invasive growth. Journal of Cell Biology, 168(3), 489–499. https://doi.org/10.1083/jcb.200403078

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