PO.BCS01.03 · 生物信息与计算
单细胞转录组学表征揭示前列腺癌双极雄激素治疗应答的通路决定因素
Single-cell transcriptomic characterisation reveals pathway determinants of bipolar androgen therapy response in prostate cancer
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摘要 Abstract
中文摘要
目的：双极雄激素治疗（BAT）在去势水平和超生理水平睾酮之间交替，代表了晚期前列腺癌中替代持续雄激素抑制的一种有前景的方案。然而，仅有一部分患者的肿瘤会产生应答。我们使用转移性去势抵抗性前列腺癌的患者来源模型，旨在利用单细胞转录组学识别区分BAT应答者与非应答者的分子程序。
实验步骤：我们使用10x Genomics单细胞RNA测序平台，对来自四个患者来源异种移植物（PDXs）的超过60,000个细胞进行了分析。用Xenocell去除小鼠读段，留下约40,000个人前列腺癌细胞用于下游分析。样本包括两名完全应答者、一名部分应答者和一名非应答者，均在BAT暴露24小时后进行评估，应答者还在长期（6周）时间点进行了评估。使用Hallmark、KEGG和基因本体论集合进行了差异表达和基因集富集（GSEA）分析。
结果：BAT在各模型中触发了稳健的雄激素应答性转录重编程，但通路激活的规模和持久性因应答类别而异。GSEA显示，应答者表现出MYC靶基因和应激反应通路的抑制，同时代谢和分化程序上调，包括氧化磷酸化、胆固醇稳态和细胞黏附。相反，非应答者维持MYC激活，伴随炎症、上皮-间质转化（EMT）和细胞周期通路的富集，提示雄激素通路重新激活不完全。随着时间推移，完全应答者显示增殖信号减少，与稳定的治疗适应一致。
结论：我们的单细胞转录组学分析描绘了BAT敏感性和耐药性背后的分子特征。MYC活性和炎症重塑成为潜在的耐药驱动因素，而代谢和分化程序则定义了持久的应答。这些见解为识别生物标志物和设计合理的联合策略以增强BAT疗效奠定了基础。
查看英文原文 English abstract
Purpose: Bipolar androgen therapy (BAT), which alternates between castrate and supraphysiological testosterone levels, represents a promising alternative to continuous androgen suppression in advanced prostate cancer. However, only a subset of patients' tumours respond. Using patient-derived models of metastatic castration-resistant prostate cancer, we aimed to identify molecular programs distinguishing BAT responders from non-responders using single-cell transcriptomics.
Experimental Procedures: We profiled over 60,000 cells from four patient-derived xenografts (PDXs) using the 10x Genomics single-cell RNA-seq platform. Mouse reads were removed with Xenocell, leaving approximately 40,000 human prostate cancer cells for downstream analysis. Samples included two complete responders, one partial responder, and one non-responder, all evaluated 24 hours after BAT exposure, with responders also assessed at a long-term (6-week) timepoint. Differential expression and gene set enrichment (GSEA) analyses were performed using Hallmark, KEGG, and Gene Ontology collections.
Results: BAT triggered robust androgen-responsive transcriptional reprogramming across models, yet the scale and persistence of pathway activation differed by response category. GSEA revealed that responders exhibited suppression of MYC target genes and stress-response pathways, alongside upregulation of metabolic and differentiation programs, including oxidative phosphorylation, cholesterol homeostasis, and cell adhesion. In contrast, the non-responder maintained MYC activation with enrichment of inflammatory, epithelial-mesenchymal transition (EMT), and cell-cycle pathways, suggesting incomplete androgen pathway re-engagement. Over time, complete responders showed reduced proliferative signalling, consistent with stable treatment adaptation.
Conclusions: Our single-cell transcriptomic analyses delineate molecular signatures underlying BAT sensitivity and resistance. MYC activity and inflammatory remodelling emerge as potential drivers of resistance, whereas metabolic and differentiation programs define durable response. These insights provide a foundation for identifying biomarkers and designing rational combination strategies to enhance BAT efficacy.
利益披露 Disclosure
R. Quezada Urban, None..
S. Keerthikumar, None..
P. Lau, None..
G. Cuffe, None..
L. Teng, None..
M. Crumbaker, None.