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Theranostics 2021; 11(13):6173-6192. doi:10.7150/thno.58254 This issue Cite

Research Paper

A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in the triple-negative breast cancer microenvironment

Lindsay B Alcaraz1, Aude Mallavialle1, Timothée David1, Danielle Derocq1, Frédéric Delolme2,3, Cindy Dieryckx2,3, Caroline Mollevi4, Florence Boissière-Michot5, Joëlle Simony-Lafontaine5, Stanislas Du Manoir1, Pitter F. Huesgen6,7, Christopher M. Overall6, Sophie Tartare-Deckert8, William Jacot1,5,9, Thierry Chardès1, Séverine Guiu1,9, Pascal Roger1,10, Thomas Reinheckel11, Catherine Moali2,3, Emmanuelle Liaudet-Coopman1✉

1. IRCM, INSERM U1194, Univ Montpellier, ICM, Montpellier, France.
2. University of Lyon, CNRS UMR5305, Tissue Biology and Therapeutic Engineering Laboratory (LBTI), F-69367 Lyon, France.
3. University of Lyon, ENS de Lyon, INSERM US8, CNRS UMS3444, SFR Biosciences, F-69366 Lyon, France.
4. Biometry department, ICM, Montpellier, France.
5. Translational Research Unit, ICM, Montpellier, France.
6. University of British Columbia, Faculty of Dentistry, Centre for Blood Research, British Columbia, V6T 1Z3, Canada.
7. Forschungszentrum Jülich, ZEA-3 Analytics, 52428 Jülich, Germany.
8. Côte d'Azur University, Inserm, C3M, Nice, France.
9. Department of Medical Oncology, ICM, Montpellier, France.
10. Department of Pathology, CHU Nîmes, Nîmes, France.
11. Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.

✉ Corresponding author: E Liaudet-Coopman, E-mail: emmanuelle.liaudet-coopmanfr.

Citation:
Alcaraz LB, Mallavialle A, David T, Derocq D, Delolme F, Dieryckx C, Mollevi C, Boissière-Michot F, Simony-Lafontaine J, Du Manoir S, Huesgen PF, Overall CM, Tartare-Deckert S, Jacot W, Chardès T, Guiu S, Roger P, Reinheckel T, Moali C, Liaudet-Coopman E. A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in the triple-negative breast cancer microenvironment. Theranostics 2021; 11(13):6173-6192. doi:10.7150/thno.58254. https://www.thno.org/v11p6173.htm
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Abstract

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Rationale: 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.

Methods: The cath-D substrate repertoire was investigated by N-Terminal Amine Isotopic Labeling of Substrates (TAILS)-based degradome analysis in a co-culture assay of TNBC cells and breast fibroblasts. Substrates were validated by amino-terminal oriented mass spectrometry of substrates (ATOMS). Cath-D and SPARC expression in TNBC was examined using an online transcriptomic survival analysis, tissue micro-arrays, TNBC cell lines, patient-derived xenografts (PDX), human TNBC samples, and mammary tumors from MMTV-PyMT Ctsd-/- knock-out mice. The biological role of SPARC and its fragments in TNBC were studied using immunohistochemistry and immunofluorescence analysis, gene expression knockdown, co-culture assays, western blot analysis, RT-quantitative PCR, adhesion assays, Transwell motility, trans-endothelial migration and invasion assays.

Results: TAILS analysis showed 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.

Conclusions: Our study establishes a novel crosstalk between proteases and matricellular proteins in the tumor microenvironment through limited SPARC proteolysis, revealing a novel targetable 9-kDa bioactive SPARC fragment for new TNBC treatments. Our study will pave the way for the development of strategies for targeting bioactive fragments from matricellular proteins in TNBC.

Keywords: matricellular protein, protease, bioactive fragment, tumor microenvironment, ECM, TNBC

Citation styles

APA
Alcaraz, L.B., Mallavialle, A., David, T., Derocq, D., Delolme, F., Dieryckx, C., Mollevi, C., Boissière-Michot, F., Simony-Lafontaine, J., Du Manoir, S., Huesgen, P.F., Overall, C.M., Tartare-Deckert, S., Jacot, W., Chardès, T., Guiu, S., Roger, P., Reinheckel, T., Moali, C., Liaudet-Coopman, E. (2021). A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in the triple-negative breast cancer microenvironment. Theranostics, 11(13), 6173-6192. https://doi.org/10.7150/thno.58254.

ACS
Alcaraz, L.B.; Mallavialle, A.; David, T.; Derocq, D.; Delolme, F.; Dieryckx, C.; Mollevi, C.; Boissière-Michot, F.; Simony-Lafontaine, J.; Du Manoir, S.; Huesgen, P.F.; Overall, C.M.; Tartare-Deckert, S.; Jacot, W.; Chardès, T.; Guiu, S.; Roger, P.; Reinheckel, T.; Moali, C.; Liaudet-Coopman, E. A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in the triple-negative breast cancer microenvironment. Theranostics 2021, 11 (13), 6173-6192. DOI: 10.7150/thno.58254.

NLM
Alcaraz LB, Mallavialle A, David T, Derocq D, Delolme F, Dieryckx C, Mollevi C, Boissière-Michot F, Simony-Lafontaine J, Du Manoir S, Huesgen PF, Overall CM, Tartare-Deckert S, Jacot W, Chardès T, Guiu S, Roger P, Reinheckel T, Moali C, Liaudet-Coopman E. A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in the triple-negative breast cancer microenvironment. Theranostics 2021; 11(13):6173-6192. doi:10.7150/thno.58254. https://www.thno.org/v11p6173.htm

CSE
Alcaraz LB, Mallavialle A, David T, Derocq D, Delolme F, Dieryckx C, Mollevi C, Boissière-Michot F, Simony-Lafontaine J, Du Manoir S, Huesgen PF, Overall CM, Tartare-Deckert S, Jacot W, Chardès T, Guiu S, Roger P, Reinheckel T, Moali C, Liaudet-Coopman E. 2021. A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in the triple-negative breast cancer microenvironment. Theranostics. 11(13):6173-6192.

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