PO.MCB07.03 · 分子与细胞生物学
条形码化的细胞状态特异性转录因子筛选鉴定出SIX1是神经母细胞瘤可塑性与耐药性的关键调控因子
Barcoded cell state specific transcription factors screen identifies SIX1 as a critical regulator of neuroblastoma plasticity and drug resistance
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摘要 Abstract
中文摘要
神经母细胞瘤（NB）以瘤内异质性为特征，至少包含两种不同的细胞类型：肾上腺素能型（ADRN）和间充质型（MES）。这些细胞状态可以自发相互转换，可能由超级增强子图谱和转录因子（TF）网络的变化所驱动。这种相互转换带来了重大的治疗挑战，因为MES型NB细胞分化程度更低、迁移性更强且更耐药，它们在治疗过程中出现并促成复发。针对某一状态（如ADRN）的治疗策略可能会遗留或筛选出更耐化疗的MES细胞，使治疗工作复杂化。理解ADRN与MES状态之间可塑性的机制，对于开发更有效的、能够预防治疗耐受和肿瘤复发并改善患者预后的治疗方法至关重要。这种MES细胞状态对标准细胞毒性治疗表现出耐受性，并与更具侵袭性、迁移性的表型相关，导致NB治疗预后不良。此外，NOTCH3信号通路驱动从ADRN向MES的转变，其中PRRX1作为关键的重编程驱动因子，将ADRN细胞的超级增强子和mRNA图谱重塑向MES状态。然而，还有哪些其他TF参与了ADRN与MES之间的转分化？还有哪些其他TF导致对细胞毒性治疗的耐受，目前仍不清楚。此外，以治疗方式靶向这些通路以预防MES转变并克服治疗耐受的最有效策略仍属未知。
查看英文原文 English abstract
Neuroblastoma (NB) is characterized by intratumoral heterogeneity, consisting of at least two distinct cell types: adrenergic (ADRN) and mesenchymal (MES). These cell states can spontaneously interconvert, potentially driven by changes in super-enhancer landscapes and transcription factor (TF) networks. This interconversion presents a significant therapeutic challenge, as MES NB cells are less differentiated, more migratory, and drug-resistant, emerging during treatment and contributing to relapse. Therapeutic strategies targeting one state (like ADRN) may leave behind or select for more chemoresistant MES cells, complicating treatment efforts. Understanding the mechanisms behind the plasticity between the ADRN and MES states is critical for developing more effective treatments that prevent therapy resistance, tumor relapse, and improve patient outcomes. This MES cell state exhibits resistance to standard cytotoxic treatments and is associated with a more aggressive, migratory phenotype, contributing to poor therapeutic outcomes in NB. Additionally, NOTCH3 signaling drives the transition from ADRN to MES, with PRRX1 acting as a key reprogramming driver that reshapes the super-enhancer and mRNA landscapes of ADRN cells toward a MES state. However, what are the other TFs are involved with the transdifferentiation between ADRN and MES? What are the other TFs are responsible for the resistance of the cytotoxic therapies remain unclear. Furthermore, the most effective strategies to therapeutically target these pathways to prevent MES transition and overcome therapy resistance remain unknown.
利益披露 Disclosure
X. Liu, None..
Y. Wu, None..
H. Lei, None..
W. Fang, None..
J. Shern, None..
Z. Liu, None..
C. Thiele, None.