Fusion of Tumor Cells with Lipid-Associated Macrophages Drives Metastatic Progression of Breast Cancer

Abstract Intratumoral heterogeneity supports cancer progression and metastasis while limiting therapeutic efficacy. Comprehensive biological characterization of heterogeneous subclones in breast cancer may hold promise in battling against this deadly disease. Using single-cell transcriptomic analysis and in situ profiling of primary tumors, metastases, and circulating tumor cells from multiple patients with breast cancer, we identified a unique EPCAM+ CD68+ TREM2+ tumor subpopulation, likely resulting from the fusion of tumor cells and lipid-associated macrophages (LAM). The presence of these tumor–LAM fusion cells in the blood or in distinct metastatic sites was significantly correlated with metastatic progression. Stable fusion clonal lines established in vitro exhibited substantially enhanced proliferation, tumor initiation, and metastasis formation in mice. Integrative molecular and functional analyses revealed a critical role for SNX10 in mediating tumor–LAM fusion. Mechanistically, SNX10 physically interacted with the phospholipid scramblase ANO6 and maintained its protein stability by suppressing proteasome-mediated degradation. Furthermore, the transcription factor CBX3 directly targeted SNX10 promoter and modulated its expression. Fusion cells accumulated abundant intracellular lipid droplets and were highly sensitive to simvastatin treatment in vitro and in vivo. Together, this study uncovered that CBX3–SNX10–ANO6 signaling facilitates generation of an aggressive tumor-LAM fusion cell subpopulation that promotes metastasis, revealing an alternative metastatic mechanism and exposing putative therapeutic vulnerabilities. Significance: Single-cell transcriptomic profiling combined with functional and clinical validation identifies fusion of tumor cells and lipid-associated macrophages mediated by the CBX3-SNX10-ANO6 axis as a potentially targetable mechanism driving cancer metastasis.