An integrated multi-omic cellular atlas of human breast cancers

Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization remains limited. We present a single cell and spatially resolved transcriptomics analysis of human breast cancers. We develop a single cell method of intrinsic subtype classification (scSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using CITE-Seq provides high-resolution immune profiles, including novel macrophage populations with high expression of PD-L1 and PD-L2 immune checkpoint ligands and associations with clinical outcome. We show that mesenchymal cells generate diverse functions and cell surface protein expression through differentiation within 3 major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into anti-tumor immune regulation. Using single cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed ‘ecotypes’, with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer.EGA study EGAS00001005173