Genomic alterations shape cell phenotypes and the structure of tumor ecosystems in poorly defined ways. To investigate these relationships, we used imaging mass cytometry to quantify the expression of 37 proteins with subcellular spatial resolution in 483 tumors from the METABRIC cohort. Single-cell analysis revealed cell phenotypes spanning epithelial, stromal and immune types. Distinct combinations of cell phenotypes and cell–cell interactions were associated with genomic subtypes of breast cancer. Epithelial luminal cell phenotypes separated into those predominantly impacted by mutations and those affected by copy number aberrations. Several features of tumor ecosystems, including cellular neighborhoods, were linked to prognosis, illustrating their clinical relevance. In summary, systematic analysis of single-cell phenotypic and spatial correlates of genomic alterations in cancer revealed how genomes shape both the composition and architecture of breast tumor ecosystems and will enable greater understanding of the phenotypic impact of genomic alterations.

基因组改变以不明确的方式塑造细胞表型和肿瘤生态系统的结构。为了研究这些关系，我们使用成像质量流式细胞术以亚细胞空间分辨率量化 METABRIC 队列中 483 个肿瘤中 37 种蛋白质的表达。单细胞分析揭示了跨越上皮、基质和免疫类型的细胞表型。细胞表型和细胞间相互作用的独特组合与乳腺癌的基因组亚型相关。上皮腔细胞表型分为主要受突变影响的和受拷贝数畸变影响的。肿瘤生态系统的几个特征，包括细胞邻域，与预后相关，说明了它们的临床相关性。总之，对癌症基因组改变的单细胞表型和空间相关性的系统分析揭示了基因组如何塑造乳腺肿瘤生态系统的组成和结构，并将有助于更好地理解基因组改变的表型影响。