文献精选 > 高引权威"类器官"文献

Human primary liver cancer-derived organoid cultures for disease modeling and drug screening.

文献信息

DOI	10.1038/nm.4438
PMID	29131160
期刊	Nature medicine
影响因子	50.0
JCR 分区	Q1
发表年份	2017
被引次数	718
关键词	原代肝癌类器官, 药物筛选, 肝细胞癌
文献类型	Journal Article
ISSN	1078-8956
页码	1424-1435
期号	23(12)
作者	Laura Broutier, Gianmarco Mastrogiovanni, Monique Ma Verstegen, Hayley E Francies, Lena Morrill Gavarró, Charles R Bradshaw, George E Allen, Robert Arnes-Benito, Olga Sidorova, Marcia P Gaspersz, Nikitas Georgakopoulos, Bon-Kyoung Koo, Sabine Dietmann, Susan E Davies, Raaj K Praseedom, Ruby Lieshout, Jan N M IJzermans, Stephen J Wigmore, Kourosh Saeb-Parsy, Mathew J Garnett, Luc Jw van der Laan, Meritxell Huch

一句话小结

本研究开发了一种新型近生理状态的原发性肝癌类器官培养系统，能够真实再现三种主要肝癌亚型的组织特征和基因组特性，为肝癌的生物标志物鉴定和药物筛选提供了有效平台。该类器官模型不仅加深了对肝癌生物学的理解，还有助于推动个性化医疗策略的发展。

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原代肝癌类器官 · 药物筛选 · 肝细胞癌

摘要

人类肝癌研究目前缺乏能够真实再现原始肿瘤病理生理的体外模型。我们最近描述了一种新颖的近生理状态的类器官培养系统，其中初级人类健康肝细胞形成长期扩展的类器官，这些类器官保持肝脏组织功能和遗传稳定性。在这里，我们将该培养系统扩展至三种最常见的原发性肝癌（PLC）亚型的原发性肝癌类器官的繁殖：肝细胞癌（HCC）、胆管癌（CC）和混合性HCC/CC（CHC）肿瘤。PLC来源的类器官培养保持了原始肿瘤的组织学结构、基因表达和基因组特征，即使在相同培养条件下经过长期扩展后，仍能区分不同的肿瘤组织和亚型。异种移植研究表明，PLC来源的类器官在体内保留了肿瘤发生潜力、组织学特征和转移特性。PLC来源的类器官适合于生物标志物的鉴定和药物筛选测试，并导致发现ERK抑制剂SCH772984作为原发性肝癌的潜在治疗剂。因此，我们展示了PLC来源类器官模型在加深对肝癌生物学理解和开发个性化医疗方法方面的广泛生物医学应用。

英文摘要

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.

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主要研究问题

1. 在不同类型的原发性肝癌中，肝脏类器官的培养是否会对肿瘤微环境的模拟产生影响？
2. 该类器官培养系统如何与现有的药物筛选方法相结合，以提高肝癌治疗的成功率？
3. 有哪些具体的生物标志物可以通过PLC衍生的类器官模型进行鉴定，从而改善个性化治疗？
4. 该研究中提到的ERK抑制剂SCH772984在其他类型肿瘤中的潜在应用如何？
5. 在未来的研究中，是否考虑将PLC衍生的类器官用于临床前研究，以验证其在真实患者中的效果？

核心洞察

研究背景和目的

原发性肝癌（PLC）是全球第二大致死癌症，且其发病率持续上升，主要与糖尿病和肥胖等风险因素有关。现有的体外模型难以准确重现肝癌的病理生理特征，因此本研究旨在建立一种新型的原发性肝癌类器官（tumoroid）培养系统，以用于疾病建模和药物筛选。

主要方法/材料/实验设计

本研究通过改进已有的健康人肝细胞类器官培养方法，成功建立了三种常见的原发性肝癌亚型（肝细胞癌HCC、胆管癌CC和混合型HCC/CC）的类器官培养。研究流程如下：

1. 患者样本收集：从手术切除的原发性肝癌组织中提取样本。
2. 组织消化：通过特定消化液处理组织，促进肿瘤细胞的分离。
3. 类器官培养：将分离的细胞接种于基质中，采用特定培养基进行培养。
4. 长期扩增：监测类器官的生长和扩增。
5. 表型和基因组分析：对类器官进行组织学、基因表达和基因组特征分析。
6. 药物筛选：测试多种抗癌药物的敏感性，筛选出有效药物。

关键结果和发现

• 成功建立了来自8名患者的原发性肝癌类器官，保持了肿瘤的组织结构、基因表达谱和基因组特征。
• 类器官能够长期扩增，并在体内移植后重建肿瘤特征。
• 通过药物筛选，发现ERK抑制剂SCH772984对原发性肝癌具有潜在的治疗效果。

主要结论/意义/创新性

本研究展示了原发性肝癌类器官在重建肿瘤特征和药物筛选中的广泛应用潜力，为理解肝癌生物学和个性化医疗方法的发展提供了新的工具。类器官模型能够保持患者特异性的遗传变异，为新药的开发和生物标志物的发现提供了可能性。

研究局限性和未来方向

• 研究中未考虑肿瘤微环境和免疫系统的影响，这可能限制了对肿瘤细胞与基质和免疫细胞相互作用的研究。
• 未来的研究应考虑将类器官与免疫细胞或基质成分结合，以更全面地模拟肝癌的生物学特性。
• 进一步验证ERK抑制剂在更大规模类器官模型中的疗效，探索其在临床中的应用潜力。

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1. Organoids lead the cancer attack. - Amber R Smith;Calvin J Kuo - Nature medicine (2017)
2. Circulating tumor cell-derived organoids: Current challenges and promises in medical research and precision medicine. - Prakash P Praharaj;Sujit K Bhutia;Sunitha Nagrath;Rhonda L Bitting;Gagan Deep - Biochimica et biophysica acta. Reviews on cancer (2018)
3. In the literature: February 2018. - Andrés Cervantes - ESMO open (2018)
4. Expansion of airway basal epithelial cells from primary human non-small cell lung cancer tumors. - Robert E Hynds;Assma Ben Aissa;Kate H C Gowers;Thomas B K Watkins;Leticia Bosshard-Carter;Andrew J Rowan;Selvaraju Veeriah;Gareth A Wilson;Sergio A Quezada;Charles Swanton; ;Sam M Janes - International journal of cancer (2018)
5. Liver and Pancreas: Do Similar Embryonic Development and Tissue Organization Lead to Similar Mechanisms of Tumorigenesis? - Elsa Ghurburrun;Ivan Borbath;Frédéric P Lemaigre;Patrick Jacquemin - Gene expression (2018)
6. Core Concept: Organoids have opened avenues into investigating numerous diseases. But how well do they mimic the real thing? - Helen Shen - Proceedings of the National Academy of Sciences of the United States of America (2018)
7. Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer. - Suk Hyung Lee;Wenhuo Hu;Justin T Matulay;Mark V Silva;Tomasz B Owczarek;Kwanghee Kim;Chee Wai Chua;LaMont J Barlow;Cyriac Kandoth;Alanna B Williams;Sarah K Bergren;Eugene J Pietzak;Christopher B Anderson;Mitchell C Benson;Jonathan A Coleman;Barry S Taylor;Cory Abate-Shen;James M McKiernan;Hikmat Al-Ahmadie;David B Solit;Michael M Shen - Cell (2018)
8. Animal models of cholangiocarcinoma. - Emilien Loeuillard;Samantha R Fischbach;Gregory J Gores;Sumera I Ilyas - Biochimica et biophysica acta. Molecular basis of disease (2019)
9. A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening. - Michael L Beshiri;Caitlin M Tice;Crystal Tran;Holly M Nguyen;Adam G Sowalsky;Supreet Agarwal;Keith H Jansson;Qi Yang;Kerry M McGowen;JuanJuan Yin;Aian Neil Alilin;Fatima H Karzai;William L Dahut;Eva Corey;Kathleen Kelly - Clinical cancer research : an official journal of the American Association for Cancer Research (2018)
10. Clinically relevant inflammatory breast cancer patient-derived xenograft-derived ex vivo model for evaluation of tumor-specific therapies. - Bedrich L Eckhardt;Maria Gagliardi;LaKesla Iles;Kurt Evans;Cristina Ivan;Xiuping Liu;Chang-Gong Liu;Glauco Souza;Arvind Rao;Funda Meric-Bernstam;Naoto T Ueno;Geoffrey A Bartholomeusz - PloS one (2018)

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