ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia.
Department of Medical Biology, The University of Melbourne, Parkville, Vic, Australia.
EMBO J. 2021 Jun 1;40(11):e107333. doi: 10.15252/embj.2020107333. Epub 2021 May 5.
To examine global changes in breast heterogeneity across different states, we determined the single-cell transcriptomes of > 340,000 cells encompassing normal breast, preneoplastic BRCA1 tissue, the major breast cancer subtypes, and pairs of tumors and involved lymph nodes. Elucidation of the normal breast microenvironment revealed striking changes in the stroma of post-menopausal women. Single-cell profiling of 34 treatment-naive primary tumors, including estrogen receptor (ER) , HER2 , and triple-negative breast cancers, revealed comparable diversity among cancer cells and a discrete subset of cycling cells. The transcriptomes of preneoplastic BRCA1 tissue versus tumors highlighted global changes in the immune microenvironment. Within the tumor immune landscape, proliferative CD8 T cells characterized triple-negative and HER2 cancers but not ER tumors, while all subtypes comprised cycling tumor-associated macrophages, thus invoking potentially different immunotherapy targets. Copy number analysis of paired ER tumors and lymph nodes indicated seeding by genetically distinct clones or mass migration of primary tumor cells into axillary lymph nodes. This large-scale integration of patient samples provides a high-resolution map of cell diversity in normal and cancerous human breast.
为了研究不同状态下乳腺异质性的全球变化,我们测定了超过 34 万个细胞的单细胞转录组,这些细胞涵盖了正常乳腺、BRCA1 基因胚系突变的癌前组织、主要乳腺癌亚型,以及肿瘤和受累淋巴结对。阐明正常乳腺微环境揭示了绝经后女性基质的显著变化。对 34 例未经治疗的原发肿瘤(包括雌激素受体 [ER] 、HER2 和三阴性乳腺癌)的单细胞分析显示,癌细胞和离散的细胞周期亚群之间存在可比的多样性。BRCA1 基因胚系突变组织与肿瘤的转录组分析突出了免疫微环境的全局变化。在肿瘤免疫景观中,增殖的 CD8 T 细胞特征是三阴性和 HER2 癌症,但不是 ER 肿瘤,而所有亚型都包含循环肿瘤相关巨噬细胞,因此可能需要不同的免疫治疗靶点。配对 ER 肿瘤和淋巴结的拷贝数分析表明,是由遗传上不同的克隆播种,还是原发性肿瘤细胞大量迁移到腋窝淋巴结。这种对患者样本的大规模整合为正常和癌变人类乳腺中的细胞多样性提供了高分辨率图谱。
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