Exosomal Release of L-Plastin by Breast Cancer Cells Facilitates Metastatic Bone Osteolysis1

• Published in: Translational oncology Vol. 12; no. 3; pp. 462 - 474
• Main Authors: Tiedemann, Kerstin, Sadvakassova, Gulzhakhan, Mikolajewicz, Nicholas, Juhas, Michal, Sabirova, Zarina, Tabariès, Sébastien, Gettemans, Jan, Siegel, Peter M., Komarova, Svetlana V.
• Format: Journal Article
• Language: English
• Published: Neoplasia Press 21-12-2018
• Subjects: Original article
• ISSN: 1936-5233
• DOI: 10.1016/j.tranon.2018.11.014

Bone metastasis from breast and prostate carcinomas is facilitated by activation of bone-resorbing osteoclasts. Using proteomics approaches, we have identified peroxiredoxin-4 (PRDX4) as a cancer-secreted mediator of osteoclastogenesis. We now report characterization of L-plastin in the conditioned media (CM) of MDA-MB-231 human breast cancer cells using immunoblotting and mass spectrometry. The osteoclastogenic potential of MDA-MB-231 CM with siRNA-silenced L-plastin was significantly reduced. L-plastin was detected in cancer-derived exosomes, and inhibition of exosomal release significantly decreased the osteoclastogenic capacity of MDA-MB-231 CM. When added to osteoclast precursors primed with RANKL for 2 days, recombinant L-plastin induced calcium/NFATc1-mediated osteoclastogenesis to the levels similar to continuous treatment with RANKL. Using shRNA, we generated MDA-MB-231 cells lacking L-plastin, PRDX4, or both and injected these cell populations intratibially in CD-1 immunodeficient mice. Micro-CT and histomorphometric analysis demonstrated a complete loss of osteolysis when MDA-MB-231 cells lacking both L-plastin and PRDX4 were injected. A meta-analysis established an increase in L-plastin and PRDX4 mRNA expression in numerous human cancers, including breast and prostate carcinomas. This study demonstrates that secreted L-plastin and PRDX4 mediate osteoclast activation by human breast cancer cells.