Exosome MS4A8 promotes bone metastasis in prostate cancer by activating NF-κB and AKT pathways through RANKL

Abstract Bone metastasis is the primary cause of death in patients with prostate cancer (PCa). In this study, we aimed to explore the mechanism by which MS4A8 mediates bone metastasis via exosomes. First, exosome proteome sequencing and detection of exosome MS4A8 expression revealed that MS4A8 was highly expressed in PCa exosomes and closely related to bone metastasis. Then, in vitro and in vivo experiments further showed that exosome MS4A8 could trigger osteolytic destruction in PCa bone metastases by enhancing the activity of osteoclasts. Furthermore, techniques such as ScRNA-seq, multicolour immunofluorescence, and co-immunoprecipitation (Co-IP) further revealed that exosome MS4A8 activates the nuclear factor kappa B (NF-κB) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways in osteoclasts of PCa bone metastases through receptor activator of nuclear factor-κB ligand (RANKL) and promoted osteoclast differentiation, resulting in a vicious cycle. Our study could provide a theoretical basis for clarifying the underlying mechanism of the occurrence and development of PCa bone metastasis and for future development of therapeutic strategies.