罕见的细胞变异性和药物诱导的重编程作为癌症药物耐药性的一种模式
Sydney M Shaffer1,2, Margaret C Dunagin1, Stefan R Torborg1,3
1Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
癌细胞可以通过罕见的转录变化自发地产生耐药性. 药物治疗通过表观遗传重编程锁定了这种抗性, 突显了罕见细胞群中的多阶段过程.
科学领域:
- 癌症学
- 细胞生物学
- 遗传学
背景情况:
- 向癌症治疗初步有效,但受药物耐药性的限制.
- 抗癌细胞的出现是实现治愈的主要障碍,
- 非遗传的罕见细胞变异性呈现出药物耐药性的潜在机制,独立于明显的遗传变异.
研究的目的:
- 研究人类黑色素瘤的单细胞转录变异性.
- 要确定这种变异性是否预测哪些细胞会抵抗药物治疗.
- 阐明药物耐药性的多阶段获得背后的机制.
主要方法:
- 单细胞RNA测序以分析转录变异性.
- 药物治疗实验以观察耐药性的发展.
- 进行表观遗传分析以研究重编程事件.
主要成果:
- 人类黑色素瘤细胞具有显著的单细胞转录变异性.
- 这种变异性预测了细胞子群的后续耐药性.
- 药物治疗诱导表观遗传重编程,通过改变分化 (SOX10损失) 和激活新的信号通路 (JUN,AP-1,TEAD) 来稳定短暂的耐药性状态.
结论:
- 癌症中耐药性是一个多阶段的过程,涉及最初的罕见细胞转录变异性,随后是药物诱导的表观遗传重编程.
- 这种在黑色素瘤中观察到的机制可能代表不同细胞类型的罕见细胞亚群的抗药性.
- 了解这些动态为开发抗癌药物耐药性的新疗法提供了框架.
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