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

• Published in: Nature communications Vol. 13; no. 1; p. 5511
• Main Authors: Geldhof, Vincent, de Rooij, Laura P. M. H., Sokol, Liliana, Amersfoort, Jacob, De Schepper, Maxim, Rohlenova, Katerina, Hoste, Griet, Vanderstichele, Adriaan, Delsupehe, Anne-Marie, Isnaldi, Edoardo, Dai, Naima, Taverna, Federico, Khan, Shawez, Truong, Anh-Co K., Teuwen, Laure-Anne, Richard, François, Treps, Lucas, Smeets, Ann, Nevelsteen, Ines, Weynand, Birgit, Vinckier, Stefan, Schoonjans, Luc, Kalucka, Joanna, Desmedt, Christine, Neven, Patrick, Mazzone, Massimiliano, Floris, Giuseppe, Punie, Kevin, Dewerchin, Mieke, Eelen, Guy, Wildiers, Hans, Li, Xuri, Luo, Yonglun, Carmeliet, Peter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 38/91; 631/250/2502; 631/67/1347; 631/67/2327; 692/4028/67/1347; Angiogenesis; Blood vessels; Breast cancer; Endothelial cells; Gene sequencing; Genes; Heterogeneity; Humanities and Social Sciences; Immune response; Immune system; Immunomodulation; Lipids; Metastases; Metformin; multidisciplinary; Patients; Peroxisome proliferator-activated receptors; Science; Science (multidisciplinary); Taxonomy; Tissue analysis; Transcriptomics; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33052-y

Since a detailed inventory of endothelial cell (EC) heterogeneity in breast cancer (BC) is lacking, here we perform single cell RNA-sequencing of 26,515 cells (including 8433 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-γ and is more abundant in peri-tumoral breast tissue. Retrospective analysis of 4648 BC patients reveals that treatment with metformin (an indirect PPAR-γ signaling activator) provides long-lasting clinical benefit and is positively associated with LIPEC abundance. Our findings warrant further exploration of this LIPEC/PPAR-γ link for BC treatment. Tumor blood vessels contribute to cancer growth, invasion and metastasis. Here, by using single cell transcriptomics, the authors report an inventory of endothelial cell heterogeneity in patients with breast cancer, including a subtype that expresses genes involved in lipid processing and is regulated by PPAR-γ.