OPG promotes lung metastasis by blocking the RANKL-RANK-CXCL10 axis to drive NK cell paucity (CRISPR)

Metastasis is the major cause of cancer-related mortality. In the lung metastasis, monocyte-derived macrophages (Mo-macs) exhibit a complex function. However, tumor cells how to derive lung metastasis through Mo-macs remains unclear. Here we show that a tumor-secreted protein osteoprotegerin (OPG) contributes to the lung metastasis of cancer depends on the Mo-macs by an in vivo screening. OPG binds with RANKL to block the signaling between RANKL-RANK on Mo-macs. RANKL-RANK signals induce Mo-macs to secrete CXCL10, recruiting NK cells to control the lung metastasis. Increased expression of OPG in the metastases is regulated by TGF-β. Consistent with our findings, enrichment of OPG amplifications was observed in metastatic cancer patients, and increased expression of OPG was also shown in the lung metastatic sites compared with the paired primary breast cancer samples. Overall, our findings reveal a mechanism of how tumor cells promote lung metastasis via inhibiting the function of Mo-macs. To identify the lung metastatic derivers dependent on the Mo-macs. Anti-Csf1R antibody was used to deplete Mo-macs and then B16F10 cells transfected with a druggable sgRNA library were injected into mice via tail vein. IgG was used as control. Last, metastases were harvested to extract genomic DNA for PCR of sgRNAs. Data was analyzed by MAGeCK.