PO.ET03.01 · 实验与分子治疗
染色质重连和转录可塑性驱动卵巢癌中一种独特的双重耐药状态
Chromatin rewiring and transcriptional plasticity drive a distinct dual-resistant state in ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：对铂类-紫杉烷联合治疗的耐药是卵巢癌（OC）的主要临床障碍，然而双重耐药的分子决定因素仍未明确定义。单药顺铂或紫杉醇耐药模型已被充分表征，但双重耐药究竟代表一种叠加状态还是一种根本上独特的状态尚不清楚。
方法：我们对A2780亲本细胞及其同源的顺铂耐药（CpR）、紫杉醇耐药（TxR）和双重耐药（TxCpR）衍生细胞进行了配对的RNA-seq和ATAC-seq。采用差异表达、染色质可及性、基序富集及增强子-启动子整合分析，以鉴定每种耐药状态特有的转录组和表观基因组特征。
结果：CpR和TxR细胞表现出预期的药物特异性适应，包括DNA修复基因（如MLH1、LIG4）的上调，或细胞骨架调节因子和药物外排转运体（如ABCB1、ALDH1A1）的上调。相比之下，TxCpR细胞形成了一种独特的转录和染色质状态，其特征为杂合的上皮-间质程序、发育通路的激活，以及对有利的单药耐药特征的选择性保留。ATAC-seq揭示TxCpR细胞中远端调控元件的广泛重塑，伴有MAFF、NFATC4、YY1和ZNF549基序的富集，提示应激反应和染色质构架调节因子的参与。整合分析鉴定出TxCpR特异性增强子，包括AIM2附近一个与CTCF相关的调控元件，提示涌现的三维染色质重构稳定了双重耐药转录程序。
结论：对顺铂和紫杉醇的双重耐药并非单药反应的组合，而是由增强子重塑和协调的转录因子网络驱动的一种重编程调控状态。该数据集提供了独特的配对RNA-seq/ATAC-seq资源，并鉴定出候选的增强子和构架依赖性，这些在多药耐药OC中可能具有治疗可靶向性。
查看英文原文 English abstract
Background: Resistance to platinum-taxane combination therapy is a major clinical barrier in ovarian cancer (OC), yet the molecular determinants of dual resistance remain poorly defined. Single-agent cisplatin- or paclitaxel-resistant models are well characterized, but whether dual resistance represents an additive or fundamentally distinct state is unknown.
Methods: We performed paired RNA-seq and ATAC-seq on A2780 parental cells and isogenic cisplatin-resistant (CpR), paclitaxel-resistant (TxR), and dual-resistant (TxCpR) derivatives. Differential expression, chromatin accessibility, motif enrichment, and enhancer-promoter integration analyses were used to identify transcriptional and epigenomic features unique to each resistance state.
Results: CpR and TxR cells exhibited expected drug-specific adaptations, including upregulation of DNA repair genes (e.g., MLH1, LIG4) or cytoskeletal regulators and drug-efflux transporters (e.g., ABCB1, ALDH1A1). In contrast, TxCpR cells formed a distinct transcriptional and chromatin state, characterized by a hybrid epithelial-mesenchymal program, activation of developmental pathways, and selective retention of advantageous single-agent resistance traits. ATAC-seq revealed extensive remodeling of distal regulatory elements in TxCpR cells, with enrichment of MAFF, NFATC4, YY1, and ZNF549 motifs, implicating stress-response and chromatin-architectural regulators. Integrative analysis identified TxCpR-specific enhancers, including a CTCF-associated regulatory element near AIM2, suggesting emergent 3D chromatin restructuring that stabilizes dual-resistance transcriptional programs.
Conclusions: Dual resistance to cisplatin and paclitaxel is not a composite of single-agent responses but a reprogrammed regulatory state driven by enhancer remodeling and coordinated transcription factor networks. This dataset provides a unique paired RNA-seq/ATAC-seq resource and identifies candidate enhancer and architectural dependencies that may be therapeutically targetable in multidrug-resistant OC.
利益披露 Disclosure
W. Choi, None..
R. Perkins, None..
J. Kang, None..
H. Lyu, None..
M. S. Jung, None..
X. Hou, None..
J. Yue, None..
W. Zhang, None.