Cathepsin D exacerbates SPARC-driven aggressiveness by limited proteolysis in triple-negative breast cancer
Alcaraz, L. B.; Mallavialle, A.; David, T.; Derocq, D.; Delolme, F.; Dieryckx, C.; Boissiere-Michot, F.; Simony-Lafontaine, J.; Du Manoir, S.; Huesgen, P.; Overall, C. M.; Tartare-Deckert, S.; Jacot, W.; Chardes, T.; Guiu, S.; Roger, P.; Reinheckel, T.; Moali, C.; Liaudet-Coopman, E.
Show abstract
Extracellular matrix (ECM) remodeling by proteases results in the release of protein fragments that promote tumor progression and metastasis. The protease cathepsin D (cath-D), a marker of poor prognosis in triple-negative breast cancer (TNBC), is aberrantly secreted in the tumor microenvironment. Using degradomic analyses by TAILS, we discovered that the matricellular protein SPARC is a substrate of extracellular cath-D. In vitro, cath-D induced limited proteolysis of SPARC C-terminal extracellular Ca2+ binding domain at acidic pH, leading to the production of SPARC fragments (34-, 27-, 16-, 9-, and 6-kDa). Similarly, cath-D secreted by TNBC cells cleaved fibroblast- and cancer cell-derived SPARC at the tumor pericellular acidic pH. SPARC cleavage also occurred in TNBC tumors. Among these fragments, only the 9-kDa SPARC fragment inhibited TNBC cell adhesion and spreading on fibronectin, and stimulated their migration, endothelial transmigration, and invasion. Our study establishes a novel crosstalk between proteases and matricellular proteins in the tumor microenvironment through limited proteolysis of SPARC, revealing a novel targetable 9-kDa bioactive SPARC fragment for new TNBC treatments.
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