基于单细胞 RNA-seq 的转录因子网络分析表明，曲古抑菌素 A 可逆转前列腺癌对多西他赛的耐药性。
Transcription factor network analysis based on single cell RNA-seq identifies that Trichostatin-a reverses docetaxel resistance in prostate Cancer.
机构信息
Department of Urology, University of Michigan Medical School, NCRC B14 RM116, Ann Arbor, MI, 48109, USA.
Unit for Laboratory Animal Medicine, University of Michigan, NCRC B14 RM116, Ann Arbor, MI, 48109, USA.
出版信息
BMC Cancer. 2021 Dec 8;21(1):1316. doi: 10.1186/s12885-021-09048-0.
BACKGROUND
Overcoming drug resistance is critical for increasing the survival rate of prostate cancer (PCa). Docetaxel is the first cytotoxic chemotherapeutical approved for treatment of PCa. However, 99% of PCa patients will develop resistance to docetaxel within 3 years. Understanding how resistance arises is important to increasing PCa survival.
METHODS
In this study, we modeled docetaxel resistance using two PCa cell lines: DU145 and PC3. Using the Passing Attributes between Networks for Data Assimilation (PANDA) method to model transcription factor (TF) activity networks in both sensitive and resistant variants of the two cell lines. We identified edges and nodes shared by both PCa cell lines that composed a shared TF network that modeled changes which occur during acquisition of docetaxel resistance in PCa. We subjected the shared TF network to connectivity map analysis (CMAP) to identify potential drugs that could disrupt the resistant networks. We validated the candidate drug in combination with docetaxel to treat docetaxel-resistant PCa in both in vitro and in vivo models.
RESULTS
In the final shared TF network, 10 TF nodes were identified as the main nodes for the development of docetaxel resistance. CMAP analysis of the shared TF network identified trichostatin A (TSA) as a candidate adjuvant to reverse docetaxel resistance. In cell lines, the addition of TSA to docetaxel enhanced cytotoxicity of docetaxel resistant PCa cells with an associated reduction of the IC50 of docetaxel on the resistant cells. In the PCa mouse model, combination of TSA and docetaxel reduced tumor growth and final weight greater than either drug alone or vehicle.
CONCLUSIONS
We identified a shared TF activity network that drives docetaxel resistance in PCa. We also demonstrated a novel combination therapy to overcome this resistance. This study highlights the usage of novel application of single cell RNA-sequencing and subsequent network analyses that can reveal novel insights which have the potential to improve clinical outcomes.
背景
克服耐药性对于提高前列腺癌（PCa）的生存率至关重要。多西他赛是第一种批准用于治疗 PCa 的细胞毒性化疗药物。然而，99%的 PCa 患者在 3 年内会对多西他赛产生耐药性。了解耐药性的产生机制对于提高 PCa 的生存率非常重要。
方法
在本研究中，我们使用两种 PCa 细胞系：DU145 和 PC3 来模拟多西他赛耐药性。使用网络间传递属性的数据同化（PANDA）方法来模拟两种细胞系的敏感和耐药变体中的转录因子（TF）活性网络。我们确定了两个 PCa 细胞系共享的边缘和节点，组成了一个共享 TF 网络，该网络模拟了 PCa 获得多西他赛耐药性过程中发生的变化。我们将共享 TF 网络提交给连接图谱分析（CMAP），以识别可能破坏耐药网络的潜在药物。我们验证了候选药物与多西他赛联合治疗体外和体内模型中的多西他赛耐药性 PCa 的效果。
结果
在最终的共享 TF 网络中，确定了 10 个 TF 节点作为多西他赛耐药性发展的主要节点。共享 TF 网络的 CMAP 分析确定曲古抑菌素 A（TSA）是逆转多西他赛耐药的候选辅助药物。在细胞系中，TSA 与多西他赛联合使用增强了多西他赛耐药 PCa 细胞的细胞毒性，同时降低了耐药细胞的多西他赛 IC50。在 PCa 小鼠模型中，与单独使用任何一种药物或载体相比，TSA 和多西他赛的联合使用可降低肿瘤生长和最终重量。
结论
我们确定了一个驱动 PCa 中多西他赛耐药性的共享 TF 活性网络。我们还展示了一种新的联合治疗方法来克服这种耐药性。这项研究强调了单细胞 RNA-seq 及其后续网络分析的新应用，这些应用可能揭示新的见解，从而有可能改善临床结果。
Zotero 插件