Tumor-derived S100A14 targeted astrocytes via TLR4 to Recruit myeloid-derived suppressor cells promoting brain metastasis and Curdione reversal effect.

BACKGROUND

Brain metastasis (BrM) is the most common complication with the highest mortality in clinical tumor patients. The underlying mechanisms of S100A14 in promoting tumor BrM remains unclear, and effective therapeutic compounds targeting S100A14 are currently unavailable.

PURPOSE: In this study, we aimed to investigate molecular mechanism of tumor-derived S100A14 targeting TLR4, activating astrocytes, and recruiting myeloid-derived suppressor cells (MDSCs) to promote tumor BrM and the underlying mechanisms of curdione in targeting S100A14 to suppress tumor BrM.

METHODS

S100A14 promoted tumor BrM effects were systematically assessed using intracardiac mice model, TMT-based quantitative proteomics and ELISA assay of clinical patients. Non-contact co-culture systems with primary astrocytes, multiplex cytokine profiling, MDSCs recruitment transwell assay were used to validate the S100A14-astrocyte-MDSCs crosstalk. Cellular Thermal Shift Assay, Drug Affinity Responsive Target Stability (DARTS) assays were adopted to elucidate the therapeutic mechanism of curdione.

RESULTS

We firstly confirmed that S100A14 was highly expressed in the serum of lung cancer patients with BrM and exhibited a strong negative correlation with breast and lung cancer overall survival. Mechanistically, S100A14 driven tumor BrM by targeting astrocytic Toll-like receptor 4, activating NF-κB signaling, reprogramming astrocytes to secrete pro-inflammatory cytokines (IL-6) and chemokines (CCL2 and CXCL1) to recruit both polymorphonuclear and monocytic MDSCs and eventually establishing brain immunosuppressive niche. Meanwhile, we identified Curdione as a potent, effective S100A14 inhibitor that reversed S100A14-mediated cascade reaction to suppress tumor BrM.

CONCLUSION

Our findings indicated that S100A14 is a clinically relevant biomarker for early detection and a potential therapeutic target for BrM.