Remodeling the aged bone marrow niche: LRG1-mediated immunosuppression promotes prostate cancer metastasis

Prostate cancer (PCa) bone metastasis arises from intricate interactions between tumor cells and the bone marrow microenvironment. Chronic inflammation in the aging bone marrow is thought to foster an immunosuppressive niche that facilitates metastatic progression. Here, we identify Leucine-Rich Alpha-2-Glycoprotein 1 (LRG1) as a central mediator of this process. LRG1 protein is significantly elevated in the circulation of patients with metastatic castration-resistant prostate cancer (mCRPC), where its levels correlate with worse overall survival. In both human PCa tissues and our established RM1-BM3 mouse model of PCa bone metastasis, LRG1 expression is markedly upregulated. Functionally, LRG1 overexpression enhances tumor growth in bone and correlates with immunosuppressive bone microenvironment by accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, MS and CO-IP assays reveal that LRG1 interacts directly with ITGA6 (CD49f) on prostate cancer cells to activate pro-metastatic pathways and with the inflammatory protein S100A9 to recruit and expand PMN-MDSCs. Furthermore, we show that interleukin-1 (IL-1) stimulates LRG1 expression in an androgen receptor (AR)-independent manner via NF-κB pathway activation. Collectively, we propose a model wherein IL-1 signaling in the aging bone marrow upregulates LRG1, which then acts dually: it promotes cancer cell aggressiveness via ITGA6 and fosters an immunosuppressive niche via S100A9-PMN-MDSC axis, thereby driving bone metastasis in CRPC. Our findings nominate LRG1 and its associated pathways as promising therapeutic targets for metastatic prostate cancer.