Organoid screening reveals epigenetic vulnerabilities in human colorectal cancer
Organoid screening reveals epigenetic vulnerabilities in human colorectal cancer
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DOI：
10.1038/s41589-022-00984-x
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发表时间：
2022-03-10
影响因子：
14.8
通讯作者：
Sato, Toshiro
中科院分区：
文献类型：
--
作者：
Toshimitsu, Kohta;Takano, Ai;Sato, Toshiro
精准肿瘤学根据肿瘤的分子特征推测药物反应的准确预测。然而，源自患者的肿瘤类器官在多大程度上概括了体内肿瘤对给定药物的反应仍不清楚。为了深入了解人类结直肠癌 (CRC) 的药理学，我们为患者来源的结直肠类器官创建了一个强大的药物筛选平台。悬浮培养的应用增加了类器官的可扩展性，并且培养条件的改进使得能够将正常和前体类器官纳入高通量药物筛选。药物筛选发现溴结构域和末端外 (BET) 溴结构域蛋白抑制剂是一种癌症选择性生长抑制剂，针对 CRC 中异常激活的基因。多组学分析确定了检查点与叉头和无名指结构域 (CHFR) 沉默和紫杉醇敏感性之间的关联，并通过类器官和异种移植物的基因工程进一步验证了这一关联。我们的研究结果强调了多参数验证在增强药物筛选系统的生物学和临床保真度方面的效用。
Precision oncology presumes an accurate prediction of drug response on the basis of the molecular profile of tumors. However, the extent to which patient-derived tumor organoids recapitulate the response of in vivo tumors to a given drug remains obscure. To gain insights into the pharmacobiology of human colorectal cancer (CRC), we here created a robust drug screening platform for patient-derived colorectal organoids. Application of suspension culture increased organoid scalability, and a refinement of the culture condition enabled incorporation of normal and precursor organoids to high-throughput drug screening. Drug screening identified bromodomain and extra-terminal (BET) bromodomain protein inhibitor as a cancer-selective growth suppressor that targets genes aberrantly activated in CRC. A multi-omics analysis identified an association between checkpoint with forkhead and ring finger domaines (CHFR) silencing and paclitaxel sensitivity, which was further validated by gene engineering of organoids and in xenografts. Our findings highlight the utility of multiparametric validation in enhancing the biological and clinical fidelity of a drug screening system.