Primary prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone metastasis

• Published in: The Journal of experimental medicine Vol. 216; no. 12; pp. 2883 - 2899
• Main Authors: Dai, Jinlu, Escara-Wilke, June, Keller, Jill M, Jung, Younghun, Taichman, Russell S, Pienta, Kenneth J, Keller, Evan T
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 02.12.2019
• Subjects: Animals; Bone Neoplasms - secondary; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Disease Models, Animal; Exosomes - metabolism; Gene Expression; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Male; Mice; Models, Biological; Prostatic Neoplasms - immunology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Pyruvate Kinase - genetics; Pyruvate Kinase - metabolism; Stromal Cells - immunology; Stromal Cells - metabolism; Tumor Burden
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20190158

Prostate cancer (PCa) metastasizes selectively to bone through unknown mechanisms. In the current study, we identified exosome-mediated transfer of pyruvate kinase M2 (PKM2) from PCa cells into bone marrow stromal cells (BMSCs) as a novel mechanism through which primary tumor-derived exosomes promote premetastatic niche formation. We found that PKM2 up-regulates BMSC CXCL12 production in a HIF-1α-dependent fashion, which subsequently enhances PCa seeding and growth in the bone marrow. Furthermore, serum-derived exosomes from patients with either primary PCa or PCa metastasis, as opposed to healthy men, reveal that increased exosome PKM2 expression is associated with metastasis, suggesting clinical relevance of exosome PKM2 in PCa. Targeting the exosome-induced CXCL12 axis diminished exosome-mediated bone metastasis. In summary, primary PCa cells educate the bone marrow to create a premetastatic niche through primary PCa exosome-mediated transfer of PKM2 into BMSCs and subsequent up-regulation of CXCL12. This novel mechanism indicates the potential for exosome PKM2 as a biomarker and suggests therapeutic targets for PCa bone metastasis.