Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Kunming Institute of Zoology, Chinese Academy of Sciences. Kunming, Yunnan, China.
Theranostics. 2024 May 19;14(8):3104-3126. doi: 10.7150/thno.96163. eCollection 2024.
The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both and experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both and experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer.
肿瘤干细胞或祖细胞通过遗传和表观遗传程序赋予癌细胞发育可塑性和独特的细胞身份。利用新技术全面描绘和绘制乳腺癌的细胞起源，以揭示新的亚型特异性治疗靶点，目前仍尚未实现。我们整合了来自正常乳腺组织的 195144 个高质量细胞和来自原发性乳腺癌样本的 406501 个高质量细胞，创建了人类正常和癌变乳腺的大规模单细胞图谱。通过将癌细胞与参考正常上皮细胞进行对比，探索恶性细胞的潜在异质性起源。进行多组学分析和实验，筛选和验证潜在的亚型特异性治疗靶点。通过免疫组化在我们的队列中验证了鉴定的免疫和基质细胞亚群的新型生物标志物。基于肿瘤细胞起源模式的肿瘤分层与临床结局、基因组异常和不同的微环境组成相关。我们发现，腔前体细胞（LP）亚型与预后不良、基因组不稳定性和功能失调的免疫微环境密切相关。然而，LP 亚型患者对新辅助化疗（NAC）、PARP 抑制剂（PARPi）和免疫疗法敏感。通过实验研究了 LP 亚型特异性靶标 PLK1。此外，乳腺癌的大规模单细胞分析启发我们鉴定了一系列具有临床意义的免疫和基质细胞亚群，包括固有淋巴细胞（ILC）、巨噬细胞和内皮细胞的亚群。本单细胞研究揭示了乳腺癌的细胞组成和肿瘤起源模式。结合单细胞和批量转录组数据，我们阐明了从正常到恶性亚型的进化模拟，并阐述了具有重要临床意义的 LP 亚型。我们研究中鉴定的乳腺癌新型免疫和基质细胞亚群可能是潜在的治疗靶点。总之，我们的研究结果为乳腺癌的精确预后和治疗分层奠定了基础。
