Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells.
Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells.
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基因调控网络拓扑控制神经胶质瘤干细胞样细胞的耐药性和治疗逃避。
DOI：
10.1101/2024.02.02.578510
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Baliga,NitinS
中科院分区：
文献类型：
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作者：
Park,JamesH;Hothi,Parvinder;LopezGarciadeLomana,Adrian;Pan,Min;Calder,Rachel;Turkarslan,Serdar;Wu,Wei-Ju;Lee,Hwahyung;Patel,AnoopP;Cobbs,Charles;Huang,Sui;Baliga,NitinS
胶质母细胞瘤(GBM)的不良预后和耐药可能是由于细胞异质性和治疗引起的肿瘤细胞表型状态的转变，包括去分化为胶质瘤干细胞(GSCs)。这种罕见的致瘤细胞亚群抵抗替莫唑胺，经历原神经到间充质的转变(PMT)以逃避治疗，并促使复发。通过在单细胞分辨率下推断患者来源的GSCs(PD-GSCs)的转录调控网络(TRN)，我们展示了转录因子相互作用网络的拓扑结构如何驱动对细胞毒药物治疗耐药或敏感的PD-GSCs细胞状态转换的不同轨迹。通过实验测试基于TRN模拟的预测，我们表明药物治疗推动PD-GSC沿着中间状态的轨迹存活，暴露了对siRNA或第二种药物靶向治疗诱导的调控非遗传细胞可塑性的转录程序增强杀伤的脆弱性。我们的发现展示了一种揭示TRN拓扑并使用它来合理预测组合治疗破坏GBM获得性耐药的方法。
Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity and treatment-induced shifts in phenotypic states of tumor cells, including dedifferentiation into glioma stem-like cells (GSCs). This rare tumorigenic cell subpopulation resists temozolomide, undergoes proneural-to-mesenchymal transition (PMT) to evade therapy, and drives recurrence. Through inference of transcriptional regulatory networks (TRNs) of patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology of transcription factor interaction networks drives distinct trajectories of cell-state transitions in PD-GSCs resistant or susceptible to cytotoxic drug treatment. By experimentally testing predictions based on TRN simulations, we show that drug treatment drives surviving PD-GSCs along a trajectory of intermediate states, exposing vulnerability to potentiated killing by siRNA or a second drug targeting treatment-induced transcriptional programs governing nongenetic cell plasticity. Our findings demonstrate an approach to uncover TRN topology and use it to rationally predict combinatorial treatments that disrupt acquired resistance in GBM.