Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.

中文翻译：

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人类原发性肝癌衍生的类器官培养物，用于疾病建模和药物筛选。


人类肝癌研究目前缺乏能够忠实再现原发肿瘤病理生理学的体外模型。我们最近描述了一种新颖的、接近生理的类器官培养系统，其中原代人类健康肝细胞形成长期扩张的类器官，保留肝组织功能和遗传稳定性。在这里，我们将该培养系统扩展到来自三种最常见 PLC 亚型的原发性肝癌 (PLC) 类器官的繁殖：肝细胞癌 (HCC)、胆管癌 (CC) 和 HCC/CC 联合肿瘤 (CHC)。 PLC衍生的类器官培养物保留了原始肿瘤的组织学结构、基因表达和基因组景观，即使在相同培养基条件下长期扩增培养后，也可以区分不同的肿瘤组织和亚型。异种移植研究表明，PLC 衍生的类器官的致瘤潜力、组织学特征和转移特性在体内得以保留。 PLC 衍生的类器官适合生物标志物鉴定和药物筛选测试，并导致 ERK 抑制剂 SCH772984 被鉴定为原发性肝癌的潜在治疗剂。因此，我们展示了 PLC 衍生的类器官模型在进一步了解肝癌生物学和开发针对该疾病的个性化医疗方法方面的广泛生物医学用途。