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.

前列腺癌（PCa）通过未知机制选择性转移至骨骼。在当前的研究中，我们发现外泌体介导的丙酮酸激酶M2（PKM2）从PCa细胞转移到骨髓基质细胞（BMSC）是一种新机制，原发性肿瘤来源的外泌体通过该机制促进转移前生态位形成。我们发现 PKM2 以 HIF-1α 依赖性方式上调 BMSC CXCL12 的产生，从而增强骨髓中 PCa 的播种和生长。此外，与健康男性相比，来自原发性 PCa 或 PCa 转移患者的血清来源的外泌体表明，外泌体 PKM2 表达增加与转移相关，这表明外泌体 PKM2 在 PCa 中具有临床相关性。靶向外泌体诱导的 CXCL12 轴可减少外泌体介导的骨转移。总之，原代 PCa 细胞通过原代 PCa 外泌体介导的 PKM2 转移至 BMSC 并随后上调 CXCL12，教育骨髓创建转移前生态位。这种新机制表明外泌体 PKM2 作为生物标志物的潜力，并提出了 PCa 骨转移的治疗靶点。