Epigenetic heterogeneity and transcriptional drivers of triple-negative breast cancer (PDX RNA-Seq)

Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity and treatment response, we combined functional and molecular profiling with computational analysis tools. Using these approaches, we defined transcriptional, epigenetic, and metabolic subtypes, and identified subtype-driving super-enhancers. Single cell RNA sequencing analyses revealed relative homogeneity of the three major transcriptional subtypes (luminal, basal and mesenchymal) within tumors. We found that mesenchymal TNBCs are more similar to mesenchymal neuroblastoma and rhabdoid tumors than to other TNBC subtypes, and the PRRX1 transcription factor serves as a key driver of these tumors. By directly regulating the transcription of mesenchymal genes, PRRX1 is sufficient for inducing the mesenchymal subtype but is not required for its maintenance. Overall design: RNA-seq of 15 TNBC patient derived xenografts

三阴性乳腺癌（triple-negative breast cancer, TNBC）是一类具有高度异质性且治疗选择有限的疾病。为解析三阴性乳腺癌的异质性与治疗响应特征，本研究将功能分析、分子谱分析与计算分析工具相结合。借助上述研究策略，我们明确了该疾病的转录组、表观基因组及代谢组亚型，并鉴定出驱动各亚型形成的超级增强子（super-enhancer）。单细胞RNA测序（single cell RNA sequencing）分析显示，肿瘤内部的三种主要转录组亚型（管腔型、基底型及间质型）呈现相对均一性。研究发现，间质型三阴性乳腺癌与间质型神经母细胞瘤、横纹肌样瘤的相似性显著高于其与其他三阴性乳腺癌亚型的相似性，且PRRX1转录因子是此类肿瘤的关键驱动因子。PRRX1可通过直接调控间质相关基因的转录，足以诱导间质型亚型的形成，但并非维持该亚型所必需。实验整体设计：对15株三阴性乳腺癌患者来源异种移植瘤开展RNA测序（RNA-seq）。