Proteomics

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A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in cancer


ABSTRACT: The remodeling of the extracellular matrix (ECM) by proteases releases 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 ECM. Using degradomics, 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). Cath-D secreted by TNBC cells cleaved fibroblast- and cancer cell-derived SPARC at the tumor pericellular pH. SPARC cleavage also occurred in TNBC tumors. Among these fragments, the 9-kDa SPARC fragment inhibited TNBC cell adhesion and spreading, and stimulated their migration, endothelial transmigration and invasion more potently than full-length SPARC. Our study establishes a novel crosstalk between proteases and matricellular proteins in the ECM through limited proteolysis of SPARC, revealing a novel targetable 9-kDa bioactive SPARC fragment for TNBC.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo sapiens  

TISSUE(S): Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Frederic DELOLME  

LAB HEAD: Emmanuelle LIAUDET-COOPMAN

PROVIDER: PXD022826 | Pride | 2021-09-09

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
200228-CD-0157-PO-Co1811.mzML Mzml
Co_cult_MDA-MB-231_vs_HMF-R1.mgf Mgf
Co_cult_MDA-MB-231_vs_HMF-R1.mzML Mzml
Co_cult_MDA-MB-231_vs_HMF-R1.raw Raw
Co_cult_MDA-MB-231_vs_HMF-R1R2R3.mgf Mgf
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Publications


<b>Rationale:</b> Alternative therapeutic strategies based on tumor-specific molecular targets are urgently needed for triple-negative breast cancer (TNBC). The protease cathepsin D (cath-D) is a marker of poor prognosis in TNBC and a tumor-specific extracellular target for antibody-based therapy. The identification of cath-D substrates is crucial for the mechanistic understanding of its role in the TNBC microenvironment and future therapeutic developments. <b>Methods</b>: The cath-D substrate r  ...[more]

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