RRC ID 59763
Author Dai J, Escara-Wilke J, Keller JM, Jung Y, Taichman RS, Pienta KJ, Keller ET.
Title Primary prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone metastasis.
Journal J Exp Med
Abstract 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.
Volume 216(12)
Pages 2883-2899
Published 2019-12-2
DOI 10.1084/jem.20190158
PII jem.20190158
PMID 31548301
PMC PMC6888980
MeSH 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
IF 10.892
Times Cited 8
Human and Animal Cells ST2(RCB0224)