Abstract
Recent evidence establishes the brain metastatic microenvironment as a key regulator of metastatic outgrowth, with oligodendrocytes being established as essential components of the brain metastatic microenvironment. Nonetheless, the mechanisms underlying oligodendrocyte-mediated brain metastasis in lung cancer await clarification. Using orthogonal experimental models spanning clinical specimens and animal models, we investigated the presence and functional roles of oligodendrocytes in lung cancer brain metastasis (LCBM). Combinatorial approaches including scRNA-seq, functional genomics, and mechanistic studies revealed ERBB3 as the critical paracrine factor mediating oligodendrocyte-tumor crosstalk. Through comprehensive analysis, we demonstrated the infiltration of oligodendrocytes in the metastatic niche of LCBM. Functional assays demonstrated that oligodendrocytes significantly enhanced the proliferation, migration, and invasion of brain metastatic cells of lung cancer. Mechanistically, oligodendrocyte-secreted ERBB3 acts as a copper chaperone that competitively mobilizes extracellular copper ions through high-affinity binding to SLC31A1 on tumor cells, thereby promoting intracellular copper accumulation. Additionally, elevated ERBB3 expression in LCBM clinical specimens correlated with significantly reduced overall survival and targeted ERBB3 suppressed lung cancer brain metastasis. Our findings establish oligodendrocyte-derived ERBB3 as a critical mediator of intercellular copper transfer via SLC31A1 binding, which coordinately drives brain metastasis progression. Therapeutic targeting of this copper signaling axis represents a promising strategy against LCBM.