Abstract
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.
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Data availability
The data that support the findings of this study are available in Supplementary Data. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD074143 (Reviewer username: reviewer_pxd074143@ebi.ac.uk, password: 71smTS4HnxaP). Unedited blot/gel images can be seen in the Supplementary Fig. 1. The gating strategy of flow cytometry can be seen in Supplementary Fig. 2.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (Grant No.82471619) and the Natural Science Foundation of Hunan Province (Grant No.2024JJ5459).
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X.C. and Y.J.-L. performed the major experiments and analyzed overall experimental data. Y.J.-L. and M.S.-Y. revised the manuscript. M.S.-Y. and Z.L.-P. assisted with the overall experiments and interpreted data. F.Y. guided the animal experiment of left ventricular injection in mice. Y.X. and Y.X. designed the experiments and revised the manuscript. Y.X. designed the experiments, curated data, and acquired funding.
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Chen, X., Ye, Ms., Peng, ZL. et al. Single-stranded DNA in the bone microenvironment promotes prostate cancer bone metastasis via the ITGA6-FAK pathway. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09929-9
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DOI: https://doi.org/10.1038/s42003-026-09929-9
