Catalytically inactive human cathepsin D triggers fibroblast invasive growth.

Valérie Laurent-Matha (1) , Sharon Maruani-Herrmann (1) , Christine Prébois (1) , Mélanie Beaujouin (1) , Murielle Glondu (1) , Agnès Noël (2) , Marie Luz Alvarez-Gonzalez (2) , Sylvia Blacher (2) , Peter Coopman (3) , Stephen Baghdiguian (4) , Christine Gilles (2) , Jadranka Loncarek (5) , Gilles Freiss (1) , Françoise Vignon (1) , Emmanuelle El Liaudet-Coopman (1)

1 Endocrinologie moléculaire et cellulaire des cancers
2 Laboratory of Tumor and Developmental Biology
3 DMIM - Dynamique moléculaire des interactions membranaires
4 UMR ISEM - Institut des Sciences de l'Evolution de Montpellier
5 Génotypes et phénotypes tumoraux

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.

Mots clés: stroma; protease; fibroblast; outgrowth; cancer; stroma.

Domaines: Cancer; Biologie cellulaire

Valérie Laurent-Matha, Sharon Maruani-Herrmann, Christine Prébois, Mélanie Beaujouin, Murielle Glondu, et al.. Catalytically inactive human cathepsin D triggers fibroblast invasive growth.. Journal of Cell Biology, 2005, 168 (3), pp.489-99. ⟨10.1083/jcb.200403078⟩. ⟨inserm-00153783⟩