Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast

Since a detailed inventory of endothelial cell (EC) heterogeneity in breast cancer (BC) is lacking, we perform single cell RNA-sequencing of 26,515 cells (including 8,433 ECs) from 9 BC patients and compare them to published EC taxonomies from lung tumors. Angiogenic ECs are phenotypically similar, while other EC subtypes are different. Predictive interactome analysis reveals known but also previously unreported receptor-ligand interactions between ECs and immune cells, suggesting an involvement of breast EC subtypes in immune responses. We also identify a capillary EC subtype (LIPEC (Lipid Processing EC)), which expresses genes involved in lipid processing that are regulated by PPAR-gamma and is more abundant in peri-tumoral breast tissue. Retrospective analysis of 4,648 BC patients reveals that treatment with metformin (an indirect PPAR-gamma agonist) provides long-lasting clinical benefit and is positively associated with LIPEC abundance. Our findings warrant further exploration of this LIPEC/PPAR-gamma link for BC treatment. single-cell RNA-seq of human breast cancer patient-derived endothelial cells (CD31+CD102+; EC-enriched dataset) and whole stroma (Viability Dye-; non-EC-enriched dataset)