Catalytically inactive human cathepsin D triggers fibroblast invasive growth.

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Laurent-Matha, Valérie | Maruani-Herrmann, Sharon | Prébois, Christine | Beaujouin, Mélanie | Glondu, Murielle | Noël, Agnès | Alvarez-Gonzalez, Marie Luz | Blacher, Sylvia | Coopman, Peter | Baghdiguian, Stephen | Gilles, Christine | Loncarek, Jadranka | Freiss, Gilles | Vignon, Françoise | Liaudet-Coopman, Emmanuelle

Edité par CCSD ; Rockefeller University Press -

International audience. The aspartyl-protease cathepsin D (cath-D) is overexpressed 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 ras-MAPK 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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