A highly resolved integrated single-cell atlas of human breast cancers.

In this study, we developed an integrated single-cell transcriptomic (scRNAseq) atlas of human breast cancer (BC), the largest resource of its kind, totaling >600 000 cells across 138 patients. Rigorous integration and annotation of publicly available scRNAseq data enabled a highly resolved characterization of epithelial, immune, and stromal heterogeneity within the tumor microenvironment (TME). Within the immune compartment, we were able to characterize heterogeneity of CD4, CD8 T cells, and macrophage subpopulations. Within the stromal compartment, subpopulations of endothelial cells (ECs) and cancer-associated fibroblasts (CAFs) were resolved. Within the cancer epithelial compartment, we characterized the functional heterogeneity of cells across the axes of stemness, epithelial-mesenchymal plasticity, and canonical cancer pathways. Across all subpopulations observed in the TME, we performed a multi-resolution survival analysis to identify epithelial cell states and immune and stromal cell types, which conferred a survival advantage in both The Cancer Genome Atlas (TCGA), METABRIC, and SCANB. We also identified robust associations between TME composition and clinical phenotypes such as tumor subtype and grade that were not discernible when the analysis was limited to individual datasets, highlighting the need for atlas-based analyses. This atlas represents a valuable resource for further high-resolution analyses of TME heterogeneity within BC.