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

Jinlu Dai, June Escara-Wilke, Jill M. Keller, Younghun Jung, Russell S. Taichman, Kenneth J. Pienta, Evan T. Keller

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2883-2899
Number of pages17
JournalThe Journal of experimental medicine
Volume216
Issue number12
DOIs
StatePublished - Dec 2 2019

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Bone Neoplasms
Exosomes
Pyruvate Kinase
Prostatic Neoplasms
Neoplasm Metastasis
Bone and Bones
Mesenchymal Stromal Cells
Up-Regulation
Bone Marrow Cells
Biomarkers
Bone Marrow

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Primary prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone metastasis. / Dai, Jinlu; Escara-Wilke, June; Keller, Jill M.; Jung, Younghun; Taichman, Russell S.; Pienta, Kenneth J.; Keller, Evan T.

In: The Journal of experimental medicine, Vol. 216, No. 12, 02.12.2019, p. 2883-2899.

Research output: Contribution to journalArticle

Dai, Jinlu ; Escara-Wilke, June ; Keller, Jill M. ; Jung, Younghun ; Taichman, Russell S. ; Pienta, Kenneth J. ; Keller, Evan T. / Primary prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone metastasis. In: The Journal of experimental medicine. 2019 ; Vol. 216, No. 12. pp. 2883-2899.
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