Lusby Ryan, Zhang Ziyi, Mahesh Arun, Tiwari Vijay K
Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University, Belfast, BT9 7BL, UK.
Institute of Molecular Medicine, University of Southern Denmark, Odense M, Denmark.
NPJ Precis Oncol. 2024 Mar 12;8(1):64. doi: 10.1038/s41698-024-00529-6.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype characterised by extensive intratumoral heterogeneity, high rates of metastasis and chemoresistance, leading to poor clinical outcomes. Despite progress, the mechanistic basis of chemotherapy resistance in TNBC patients remains poorly understood. Here, leveraging single-cell transcriptome datasets of matched longitudinal TNBC chemoresponsive and chemoresistant patient cohorts, we unravel distinct cell subpopulations intricately associated with chemoresistance and the signature genes defining these populations. Notably, using genome-wide mapping of the H3K27ac mark, we show that the expression of these chemoresistance genes is driven via a set of TNBC super-enhancers and associated transcription factor networks across TNBC subtypes. Furthermore, genetic screens reveal that a subset of these transcription factors is essential for the survival of TNBC cells, and their loss increases sensitivity to chemotherapeutic agents. Overall, our study has revealed epigenetic and transcription factor networks underlying chemoresistance and suggests novel avenues to stratify and improve the treatment of patients with a high risk of developing resistance.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，其特征为肿瘤内广泛的异质性、高转移率和化疗耐药性，导致临床预后较差。尽管取得了进展，但TNBC患者化疗耐药的机制基础仍知之甚少。在此，利用匹配的纵向TNBC化疗敏感和化疗耐药患者队列的单细胞转录组数据集，我们揭示了与化疗耐药复杂相关的不同细胞亚群以及定义这些群体的特征基因。值得注意的是，通过对H3K27ac标记进行全基因组定位，我们表明这些化疗耐药基因的表达是由一组TNBC超级增强子和跨TNBC亚型的相关转录因子网络驱动的。此外，基因筛选显示这些转录因子的一个子集对TNBC细胞的存活至关重要，它们的缺失会增加对化疗药物的敏感性。总体而言，我们的研究揭示了化疗耐药背后的表观遗传和转录因子网络，并提出了对有耐药高风险患者进行分层和改善治疗的新途径。
