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Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies. ​

文献信息 ​

DOI10.1016/j.celrep.2018.07.001
PMID30067989
期刊Cell reports
影响因子6.9
JCR 分区Q1
发表年份2018
被引次数253
关键词生物样本库, 胆管细胞癌, 药物反应, 遗传异质性, 肝细胞癌
文献类型Journal Article, Research Support, Non-U.S. Gov't
页码1363-1376
期号24(5)
作者Sandro Nuciforo, Isabel Fofana, Matthias S Matter, Tanja Blumer, Diego Calabrese, Tujana Boldanova, Salvatore Piscuoglio, Stefan Wieland, Femke Ringnalda, Gerald Schwank, Luigi M Terracciano, Charlotte K Y Ng, Markus H Heim

一句话小结 ​

本研究通过从不同病因和肿瘤阶段的肝细胞癌（HCC）患者的肿瘤针刺活检中生成长期类器官培养，成功保留了肿瘤的遗传异质性和标志物表达，进而展示了类器官在评估索拉非尼敏感性方面的应用潜力。这一研究为HCC的个性化治疗提供了新的工具和思路，具有重要的临床意义。

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生物样本库 · 胆管细胞癌 · 药物反应 · 遗传异质性 · 肝细胞癌

摘要 ​

肝细胞癌（HCC）是最常见的原发性肝癌，也是全球癌症相关死亡的第二大原因。多激酶抑制剂索拉非尼是晚期HCC的唯一治疗选择。由于肿瘤的异质性，其疗效在患者之间差异显著，并且受到不良反应和药物耐药性的限制。目前的体外模型无法重现HCC的关键特征。我们报告了从不同病因和肿瘤阶段的HCC患者的肿瘤针刺活检中生成长期类器官培养。HCC类器官保留了HCC肿瘤标志物的形态和表达模式，并保持了来源肿瘤的遗传异质性。在一项原理验证研究中，我们展示了肝癌类器官可以用于测试对索拉非尼的敏感性。总之，类器官模型可以从肝癌的针刺活检中获得，为开发个性化治疗提供了工具。

英文摘要 ​

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second most frequent cause of cancer-related mortality worldwide. The multikinase inhibitor sorafenib is the only treatment option for advanced HCC. Due to tumor heterogeneity, its efficacy greatly varies between patients and is limited due to adverse effects and drug resistance. Current in vitro models fail to recapitulate key features of HCCs. We report the generation of long-term organoid cultures from tumor needle biopsies of HCC patients with various etiologies and tumor stages. HCC organoids retain the morphology as well as the expression pattern of HCC tumor markers and preserve the genetic heterogeneity of the originating tumors. In a proof-of-principle study, we show that liver cancer organoids can be used to test sensitivity to sorafenib. In conclusion, organoid models can be derived from needle biopsies of liver cancers and provide a tool for developing tailored therapies.

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主要研究问题 ​

  1. 在肝细胞癌的类器官模型中，如何评估不同药物的敏感性？
  2. 类器官模型在研究肝细胞癌异质性方面有哪些优势？
  3. 如何通过类器官技术改进肝细胞癌的个性化治疗方案？
  4. 肝细胞癌类器官与传统细胞培养模型相比，有哪些显著的生物学差异？
  5. 在类器官研究中，如何处理肝细胞癌样本的遗传多样性？

核心洞察 ​

研究背景和目的 ​

肝细胞癌（HCC）是最常见的原发性肝癌，也是全球癌症相关死亡的第二大原因。当前针对晚期HCC的治疗选择有限，主要依赖于多靶点酪氨酸激酶抑制剂索拉非尼（sorafenib），但由于肿瘤异质性，其疗效在不同患者间差异显著。本文旨在通过从HCC患者的肿瘤针刺活检中生成长期培养的类器官（organoid），为HCC的个体化治疗提供新工具。

主要方法/材料/实验设计 ​

  1. 样本收集：使用超声引导的同轴针穿刺技术从HCC患者的肿瘤及非肿瘤肝组织中收集活检样本。
  2. 类器官培养：对活检样本进行有限消化，以保留细胞间接触，促进类器官的形成。
  3. 组织学和基因组分析：通过免疫组化和全外显子测序（WES）分析类器官与原始肿瘤的形态学和基因组特征。
Mermaid diagram

关键结果和发现 ​

  • 成功从8名患者的HCC肿瘤中建立了10条类器官线，类器官保持了原肿瘤的形态和基因组特征。
  • 类器官在体外对索拉非尼表现出不同的敏感性，IC50值在2.0至5.0μM之间。
  • 通过小鼠移植实验，类器官能够形成与原肿瘤相似的肿瘤。

主要结论/意义/创新性 ​

研究表明，HCC类器官可以有效地保持原肿瘤的形态学和遗传异质性，提供了一个新的平台用于药物敏感性测试和个体化治疗的开发。该研究为HCC的生物医学研究和临床应用开辟了新的方向，特别是在个体化医疗和靶向治疗方面。

研究局限性和未来方向 ​

  • 类器官的成功率为26%，相对较低，未来需要优化培养条件以提高成功率。
  • 目前的类器官库主要基于晚期肝癌，未来应扩大样本范围，包含不同分期和分型的肝癌。
  • 进一步的研究应探索类器官在不同药物敏感性测试中的应用，以实现更精准的个体化治疗。

总结表格 ​

项目内容
研究对象肝细胞癌患者的肿瘤和非肿瘤肝组织样本
主要方法超声引导针穿刺活检、类器官培养、组织学分析、全外显子测序
关键发现类器官保持原肿瘤特征，能用于药物敏感性测试
主要结论提供了个体化治疗的新工具，类器官能有效反映肿瘤异质性
未来方向优化培养条件、扩大样本库、探索药物敏感性测试的临床应用

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引用本文的文献 ​

  1. Organoid technology and applications in cancer research. - Hanxiao Xu;Xiaodong Lyu;Ming Yi;Weiheng Zhao;Yongping Song;Kongming Wu - Journal of hematology & oncology (2018)
  2. Platinum Resistance in Ovarian Cancer: Role of DNA Repair. - Giovanna Damia;Massimo Broggini - Cancers (2019)
  3. Organoid models for translational pancreatic cancer research. - Hervé Tiriac;Dennis Plenker;Lindsey A Baker;David A Tuveson - Current opinion in genetics & development (2019)
  4. Remodelling and Improvements in Organoid Technology to Study Liver Carcinogenesis in a Dish. - Umesh Tharehalli;Michael Svinarenko;André Lechel - Stem cells international (2019)
  5. Application of Cancer Organoid Model for Drug Screening and Personalized Therapy. - Jumpei Kondo;Masahiro Inoue - Cells (2019)
  6. Liver organoids: from basic research to therapeutic applications. - Nicole Prior;Patricia Inacio;Meritxell Huch - Gut (2019)
  7. Hepatocellular Carcinoma Xenografts Established From Needle Biopsies Preserve the Characteristics of the Originating Tumors. - Tanja Blumer;Isabel Fofana;Matthias S Matter;Xueya Wang;Hesam Montazeri;Diego Calabrese;Mairene Coto-Llerena;Tujana Boldanova;Sandro Nuciforo;Venkatesh Kancherla;Luigi Tornillo;Salvatore Piscuoglio;Stefan Wieland;Luigi M Terracciano;Charlotte K Y Ng;Markus H Heim - Hepatology communications (2019)
  8. Gene manipulation in liver ductal organoids by optimized recombinant adeno-associated virus vectors. - Jinsong Wei;Gai Ran;Xin Wang;Ning Jiang;Jianqing Liang;Xinhua Lin;Chen Ling;Bing Zhao - The Journal of biological chemistry (2019)
  9. A Pharmacogenomic Landscape in Human Liver Cancers. - Zhixin Qiu;Hong Li;Zhengtao Zhang;Zhenfeng Zhu;Sheng He;Xujun Wang;Pengcheng Wang;Jianjie Qin;Liping Zhuang;Wei Wang;Fubo Xie;Ying Gu;Keke Zou;Chao Li;Chun Li;Chenhua Wang;Jin Cen;Xiaotao Chen;Yajing Shu;Zhao Zhang;Lulu Sun;Lihua Min;Yong Fu;Xiaowu Huang;Hui Lv;He Zhou;Yuan Ji;Zhigang Zhang;Zhiqiang Meng;Xiaolei Shi;Haibin Zhang;Yixue Li;Lijian Hui - Cancer cell (2019)
  10. Disease modelling in human organoids. - Madeline A Lancaster;Meritxell Huch - Disease models & mechanisms (2019)

... (243 更多 篇文献)

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