Nature Genetics:压力使癌细胞变强?研究发现压力刺激增强神经胶质瘤适应性,帮助其逃避药物治疗

2021-10-10 “生物世界”公众号 “生物世界”公众号

近日,美国康涅狄格大学健康中心和杰克逊实验室的研究人员在 Nature Genetics 期刊上发表了题为:Single-cell multimodal glioma analyses identif

孟子曰:“故天将降大任于是人也,必先苦其心志,劳其筋骨,饿其体肤,空乏其身,行拂乱其所为”。压力和动力既相互拮抗,又能相互转化,有些时候,压力不但不会压垮你,反而促使你快速成长。

但你是否想过,压力也会促使癌细胞变强,更难以被治愈?

近日,美国康涅狄格大学健康中心和杰克逊实验室的研究人员在 Nature Genetics 期刊上发表了题为:Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response 的研究论文。

这项研究表明,在压力应激环境下,例如化疗药物攻击,神经胶质瘤细胞可以通过表观遗传修饰的方式动态地修改自己的基因,改变自身基因表达模式,从而获得更强的适应能力,以逃避抗癌药物的治疗。

胶质母细胞瘤,是一种极具破坏性的脑肿瘤,它起源于脑部胶质细胞,同时也是一种颅内常见的恶性肿瘤。这种脑癌细胞与正常的大脑神经细胞缠绕并粘附在一起,这使得它们很难被手术清除。而胶质瘤这个名字在拉丁语中的意思就是“像胶水一样的肿瘤”。

胶质母细胞瘤的发病率约为3~4例/10万人,据此估算,我国每年新发胶质母细胞瘤患者约为4-5万。胶质母细胞瘤的治疗通常包括手术、放疗和化疗。但不幸的是,这类肿瘤很难根除,在一段时间的治疗之后往往会不可避免地衍生出耐药性,使得抗癌药物再难起作用。

耐药性源于肿瘤异质性,而肿瘤异质性通常由不同的遗传、表观遗传和转录畸变的亚细胞群所驱动。因此,了解胶质母细胞瘤如何在压力环境下获得异质性,并对此设计新的治疗方案,是十分重要的。

在这项研究中,研究团队首先注意到胶质母细胞瘤容易发生表观遗传修饰的改变,尤其是DNA甲基化。此前的研究证实,随机的DNA甲基化改变有助于肿瘤异质性和细胞可塑性,从而推动抗治疗表型的进化。

基于此,研究团队整合了11例胶质瘤患者样本的914个单细胞DNA甲基化组、55284个单细胞转录组和大量多组学分析,以描述肿瘤内异质性的来源,定义有助于肿瘤进化的表观遗传状态。

研究模式图

研究人员将这些体内分析与体外扰动结合起来,以确定最易受随机DNA甲基化改变影响的基因调控区域,参与胶质瘤细胞识别的转录网络的表观遗传调节,以及DNA甲基化紊乱可能促进的细胞应激反应。

研究结果显示,在胶质母细胞瘤中,局部DNA甲基化紊乱与细胞-细胞DNA甲基化差异有关,且在侵袭性更强的肿瘤中升高,这与与转录中断相联系,并在环境应激反应中发生改变。

单细胞DNA测序强调了表观遗传肿瘤内异质性和局部DNA甲基化紊乱之间的关联

不仅如此,胶质瘤细胞在体外缺氧和辐射胁迫条件下增加了局部DNA甲基化紊乱并改变了细胞状态。此外,研究人员还发现,胶质瘤细胞的遗传和表观遗传不稳定性之间存在正相关关系,这在大量纵向收集的DNA甲基化数据中得到了支持。

基因调控元件的DNA甲基化紊乱与细胞识别和应激反应途径有关

更重要的是,在压力应激环境下,例如化疗药物或辐射攻击,胶质瘤细胞中与加速疾病进展相关的DNA甲基化紊乱增加,与生存相关的DNA甲基化变化会在环境应激反应途径中不断富集,最终使得胶质瘤细胞获得更强的适应能力。

在抗肿瘤治疗应激下,胶质母细胞瘤发生适应性的DNA甲基化变化

本研究的主要领导者 Roel G. W. Verhaak 博士表示:“这篇论文强调了一种机制,通过这种机制,肿瘤细胞可能适应了我们的治疗方法。了解肿瘤使用的这些伎俩,我们可以更有效地治疗它们。这项革命性的工作确实让我们对多形性胶质母细胞瘤有了更深刻的认识。”

原始出处:

Johnson, K.C., Anderson, K.J., Courtois, E.T. et al. Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response. Nat Genet 53, 1456–1468 (2021). https://doi.org/10.1038/s41588-021-00926-8.

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    2022-08-24 liye789132251
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  5. 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2021, time=2021-10-12, status=1, ipAttribution=)]
    2021-10-22 huperzia
  7. 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2021, time=2021-10-12, status=1, ipAttribution=)]
    2022-01-10 canlab
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  9. 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    2021-10-12 yxch36
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