SERINC2-mediated phosphatidylserine remodeling activates protrusion-localized AXL signaling to promote brain metastasis.

Cell protrusions (CPs) promote metastasis by coordinating cell invasion, matrix remodeling, and communication with the microenvironment. The receptor tyrosine kinase AXL, activated in brain-tropic metastatic cancers, frequently localizes to CPs. The metabolic cues regulating CP biogenesis and AXL activation remain unclear. Here, we report that in invading cancer cells, phosphatidylserine is the most enriched lipid class in CPs. Mechanistically, we demonstrate that the scramblase-like transmembrane protein SERINC2 functions as a scaffold that interacts with integrins and recruits OSBPL8, an ER-plasma-membrane phosphatidylserine transporter, to CPs. This recruitment leads to phosphatidylserine accumulation and externalization at CPs, activation of CP-localized AXL, and upregulation of cell invasion. Furthermore, extracellular vesicles enriched in phosphatidylserine in a SERINC2-dependent manner stimulate autocrine AXL activation and drive M2-like microglia polarization. Accordingly, SERINC2 enhances orthotopic brain tumor growth and microglial reprogramming in vivo. Our data reveal a SERINC2-OSBPL8 axis orchestrating spatial lipid remodeling, AXL activation, and tumor-microenvironment communication.