Nature子刊:利用类器官,高栋团队等揭开胰腺癌染色质开放性特征

2022-05-22 生物世界 生物世界

该研究通过类器官模型系统性揭示胰腺癌的染色质开放性特征,通过整合基因组学、转录组学和药物敏感性等多组学数据揭示了不同亚型胰腺癌的基因调控网络及潜在治疗靶点。

胰腺癌是恶性程度最高的肿瘤之一,5年生存率仅为9%。尽管针对胰腺癌的基因组学及转录组学研究已极大地丰富了对其生物学行为的认知,但在进一步指导治疗方面作用十分有限。染色质开放性蕴含大量基因表达调控信息,是肿瘤演进过程的直接反馈,并且多为可逆的药物靶点。

近年来,不断深入的全肿瘤染色质开放性研究为几乎所有癌种的全新认知和靶向治疗提供了崭新的方向,但唯独胰腺癌受限于极为丰富且复杂的间质成分,系统性的染色质开放性研究始终停滞不前。因此,利用类器官(Organoids)模型深入探索胰腺癌染色质开放性特征,并整合分析基因组学、转录组学及药物敏感性等多组学数据,揭示不同亚型胰腺癌的基因调控网络及潜在药物靶点具有重要科学价值和临床应用前景。

近日,中国科学院分子细胞科学卓越创新中心(生物化学与细胞生物学研究所)高栋研究组、陈洛南研究组与海军军医大学第一附属医院(上海长海医院)金钢团队、中国科学院数学与系统科学研究院王勇研究组合作,在 Nature Communications 期刊在线发表了题为:Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity的研究论文。

该研究通过构建胰腺肿瘤类器官和正常胰腺组织类器官,首次系统性揭示胰腺癌的染色质开放性特征,并通过整合基因组学、转录组学和药物敏感性等多组学数据提出不同亚型胰腺癌的基因调控网络及潜在治疗靶点。

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研究团队构建了包含84例胰腺肿瘤类器官(75例导管腺癌、4例导管内乳头状粘液性肿瘤、1例腺泡细胞癌与4例神经内分泌肿瘤)及6例正常胰腺组织类器官的生物库,系统性收集了全基因组学、转录组学、染色质开放性、药物敏感性信息及临床大数据。

转录组学生信分析揭示了在胰腺肿瘤类器官中,除神经内分泌肿瘤亚型外,主要存在4种亚型,其中3种与既往研究完全一致(经典型、基底样型、经典-祖细胞型),并定义1种新的糖代谢亚型。该转录组学研究结果在公共数据库中得到充分验证,且能够很好地区分患者预后。进一步结合染色质开放性数据分析发现,在神经内分泌肿瘤中富集ASCL1、NKX2-5、NEUROD1、NKX6-1、POU3F2等基因表达调节子,这与近期 Cell 发表的神经内分泌肿瘤类器官培养的研究结果非常相似。而在胰腺癌的4个亚型中,分别富集HNF4A、HNF4G(经典型),TP63、HOX家族、FOXA1(基底样型),MYB、ATOH1、MYC(经典-祖细胞型)及NFE2、MAFK、PAX8(糖代谢型)等基因表达调节子。

整合和分析染色质开放性、转录组学及全基因组学等多组学数据,发现在大量的非编码区突变中,约有1516(0.63%)存在对肿瘤基因表达的调控作用,并可能是驱动肿瘤发生的超级启动子。进一步整合染色质开放性、转录组学及药物敏感性数据分析,发现丰富的染色质开放位点与药物之间存在靶向作用关系,这对发掘新的药物治疗靶点具有重要指导作用。通过对比类器官化疗药物敏感性与对应患者临床用药情况,可靠地证实了类器官模型在化疗药物敏感性上与临床治疗效果保持高度一致,并在体内模型中得到充分验证。

该研究通过类器官模型系统性揭示胰腺癌的染色质开放性特征;通过整合基因组学、转录组学和药物敏感性等多组学数据揭示了不同亚型胰腺癌的基因调控网络及潜在治疗靶点;提示染色质开放性对于深入认识胰腺癌生物学行为的极大价值,为发掘胰腺癌新的治疗靶点和治疗策略奠定了坚实基础。

分子细胞卓越中心高栋研究员、上海长海医院肝胆胰脾外科金钢教授、中国科学院数学与系统科学研究院王勇研究员、分子细胞卓越中心陈洛南研究员为该论文的共同通讯作者。上海长海医院肝胆胰脾外科时霄寒主治医师、分子细胞卓越中心李允广博士后、中国科学院数学与系统科学研究院苑秋月博士研究生、分子细胞卓越中心唐诗婕博士研究生、上海长海医院肝胆胰脾外科郭世伟副教授为该论文的共同第一作者。

论文链接:

https://www.nature.com/articles/s41467-022-29857-6

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    2022-12-31 liye789132251
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    2022-05-22 ms5000000644045955

    不错学习了。

    0

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