细胞状态可塑性来自AP-1网络内的共同调节,竞争和可配置的相互作用
Yonatan N Degefu1, Magda Bujnowska2,3, Douglas G Baumann1,4
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
bioRxiv : the preprint server for biology
|November 24, 2025
概括
黑色素瘤中的细胞状态可塑性是由AP-1转录因子控制的. 我们的模型揭示了AP-1网络动态如何驱动不同的细胞状态和治疗抵抗,提供新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 计算生物学 计算生物学
- 分子生物学分子生物学
背景情况:
- 细胞状态可塑性是黑色素瘤转移和治疗耐药性的关键驱动因素.
- AP-1转录因子网络参与调节这些塑性行为,沿着一种类似于黑色素细胞到半细胞的连续体.
- 通过AP-1网络编码离散细胞状态的精确机制,它们的种群特异分布,以及状态过渡的驱动因素仍然不完全理解.
研究的目的:
- 开发AP-1网络的机械模型,以了解其在黑色素瘤细胞状态可塑性中的作用.
- 阐明AP-1网络特征如何解释细胞状态在不同黑色素瘤种群中观察到的分布.
- 调查MAPK信号传递,AP-1状态和治疗耐药性的出现之间的联系.
主要方法:
- 开发了AP-1网络的机械普通微分方程 (ODE) 模型,考虑了二分化,共同调节和竞争性相互作用.
- 通过从遗传多样化的黑色素瘤种群中获得异质单细胞数据对模型进行了校准.
- 将模型与统计学习技术集成,并对模型预测进行实验验证.
主要成果:
- 该模型确定了特定的AP-1网络特征,这些特征解释了黑色素瘤种群中AP-1状态分布的变化.
- 发现这些网络特征与MAPK活动和克隆内变异性相关,在MAPK信号和AP-1状态之间建立了联系.
- 该模型预测,实验证实,MAPK抑制会诱导一种不分化,耐治疗的状态,这种状态可以通过AP-1向干预来缓解.
结论:
- AP-1网络作为一个可配置的系统,能够驱动黑色素瘤中的细胞状态可塑性.
- 这项研究提供了一个计算框架,用于预测和调节AP-1驱动的细胞状态转换.
- 这些发现提供了潜在的新策略,通过准AP-1网络来克服黑色素瘤的治疗耐药性.
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