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Abstract：
Triple-negative breast cancer (TNBC) is a particularly aggressive mammary neoplasia with a high fatality rate, mainly because of the development of resistance to administered chemotherapy, the standard treatment for this disease. In this study, we employ both bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) to investigate the transcriptional landscape of TNBC cells cultured in two-dimensional monolayers or three-dimensional spheroids, before and after developing resistance to the chemotherapeutic agents paclitaxel and doxorubicin. Our findings reveal significant transcriptional heterogeneity within the TNBC cell populations, with the scRNA-seq identifying rare subsets of cells that express resistance-associated genes not detected by the bulk RNA-seq. Furthermore, we observe a partial shift towards a highly mesenchymal phenotype in chemoresistant cells, suggesting the epithelial-to-mesenchymal transition (EMT) as a prevalent mechanism of resistance in subgroups of these cells. These insights highlight potential therapeutic targets, such as the PDGF signaling pathway mediating EMT, which could be exploited in this setting. Our study underscores the importance of single-cell approaches in understanding tumor heterogeneity and developing more effective, personalized treatment strategies to overcome chemoresistance in TNBC.
摘要：
三阴性乳腺癌（TNBC）是一种特别侵袭性的乳腺肿瘤，病死率高，主要是因为对化疗的耐药性的发展，这种疾病的标准治疗方法。在这项研究中,我们采用批量RNA测序和单细胞RNA测序（scRNA-seq）来研究在二维单层或三维球体中培养的TNBC细胞的转录景观，在对化疗药物紫杉醇和阿霉素产生耐药性之前和之后。我们的发现揭示了TNBC细胞群体内显著的转录异质性，用scRNA-seq鉴定表达抗性相关基因的细胞的稀有亚群，这些基因未被批量RNA-seq检测到。此外，我们观察到化学抗性细胞中的高度间充质表型的部分转变，提示上皮-间质转化（EMT）是这些细胞亚群耐药的普遍机制。这些见解突出了潜在的治疗目标，如PDGF信号通路介导EMT，可以在此设置中利用。我们的研究强调了单细胞方法在理解肿瘤异质性和开发更有效的方法中的重要性。克服TNBC化疗耐药的个性化治疗策略。
