美国系统生物系Nicholas E. Navin小组揭示了结合单细胞基因组和转录组解码乳腺癌进展。该项研究成果发表在2025年9月4日出版的《细胞》上。

为了实现这一目标，课题组开发了wellDR-seq，这是一种高基因组分辨率、高通量的方法，可以同时分析单细胞的基因组和转录组。该课题组分析了来自12例雌激素受体阳性乳腺癌的33,646个单细胞，并在多个患者中确定了祖先亚克隆，这些亚克隆显示出腔内激素反应谱系，表明可能的细胞起源。与大量研究相比，wellDR-seq能够研究亚克隆水平的基因-剂量关系，该研究显示，在大染色体片段和单基因水平上的广泛变异中，基因-剂量关系呈近线性相关。研究人员鉴定了剂量敏感基因和剂量不敏感基因，包括许多乳腺癌基因以及非癌细胞中零星的拷贝数畸变。总的来说，这些数据揭示了单细胞中拷贝数和基因表达之间的复杂关系，提高了他们对乳腺癌进展的理解。

据悉，了解乳腺癌的上皮谱系和基因型-表型关系需要对同一单细胞的基因组和转录组进行直接测量。

附：英文原文

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

Author: 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

Issue&Volume: 2025-09-04

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.

DOI: 10.1016/j.cell.2025.08.012

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00926-2