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Coalescing single-cell genomes and transcriptomes to decode breast cancer progression.

Kaile Wang·Rui Ye·Shanshan Bai·Zhenna Xiao·Lei Yang·Jianzhuo Li·Chenling Tang·Emi Sei·Jinyu Peng·Anna K Casasent·Steven H Lin·Chandandeep Nagi·Alastair M Thompson·Savitri Krishnamurthy·Nicholas E Navin
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Abstract

Understanding epithelial lineages of breast cancer and genotype-phenotype relationships requires direct measurements of the genome and transcriptome of the same single cells at scale. To achieve this, we developed wellDR-seq, a high-genomic-resolution, high-throughput method to simultaneously profile the genome and transcriptome of thousands of single cells. We profiled 33,646 single cells from 12 estrogen-receptor-positive breast cancers and identified ancestral subclones in multiple patients that showed a luminal hormone-responsive lineage, indicating a potential cell of origin. In contrast to bulk studies, wellDR-seq enabled the study of subclone-level gene-dosage relationships, which showed near-linear correlations in large chromosomal segments and extensive variation at the single-gene level. We identified dosage-sensitive and dosage-insensitive genes, including many breast cancer genes as well as sporadic copy-number aberrations in non-cancer cells. Overall, these data reveal complex relationships between copy number and gene expression in single cells, improving our understanding of breast cancer progression.

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Breast NeoplasmsHumansGenome, HumanSingle-Cell Gene Expression AnalysisTranscriptomeDisease ProgressionGene Expression Regulation, NeoplasticCell Line, TumorBase SequenceGenotypeDNA Copy Number VariationsMultigene FamilyDNA copy numberaneuploidybreast cancer genomicsbreast cancer progressiongene dosage effectssingle-cell DNA and RNA sequencingsingle-cell multiomicssingle-cell sequencingtumor evolutionwellDR-seqJournal Article

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Kaile Wang, Rui Ye, Shanshan Bai, Zhenna Xiao, Lei Yang, Jianzhuo Li, Chenling Tang, Emi Sei, Jinyu Peng, Anna K Casasent, Steven H Lin, Chandandeep Nagi, Alastair M Thompson, Savitri Krishnamurthy, Nicholas E Navin. 2025-09-04. Coalescing single-cell genomes and transcriptomes to decode breast cancer progression.. https://doi.org/10.1016/j.cell.2025.08.012

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