Single-stranded DNA in the bone microenvironment promotes prostate cancer bone metastasis via the ITGA6-FAK pathway

Bone metastases represent a critical phenotype of prostate cancer progression, driven by factors within the bone microenvironment. However, the molecular mechanisms underlying this progression remain poorly understood. In this study, we observed a significant accumulation of single-stranded DNA within the metastatic bone microenvironment of PCa patients. Through cell-SELEX methodology, we identified a PCa target-specific ssDNA, EHBP1. Specifically, EHBP1-ssDNA specifically captures PCa cells by binding to the transmembrane protein integrin α6, which subsequently activates the integrin α6-FAK signaling pathway. Functional studies revealed that knockdown of integrin-α6 expression effectively abrogated EHBP1-ssDNA mediated PCa bone metastatic capacity. Notably, these findings were recapitulated through pharmacological inhibition of FAK signaling using Defactinib, an FAK-specific inhibitor. Taken together, our findings reveal that bone-marrow ssDNA may represent a bone microenvironment factor that captures and promotes PCa homing to bone, further suggesting a potential therapeutic strategy for mitigating bone metastasis.