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Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. ​

文献信息 ​

DOI10.1038/nm.3585
PMID24859528
期刊Nature medicine
影响因子50.0
JCR 分区Q1
发表年份2014
被引次数257
关键词原代类器官, 癌变, 肠道组织, 驱动癌基因, 肿瘤模型
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN1078-8956
页码769-77
期号20(7)
作者Xingnan Li, Lincoln Nadauld, Akifumi Ootani, David C Corney, Reetesh K Pai, Olivier Gevaert, Michael A Cantrell, Paul G Rack, James T Neal, Carol W-M Chan, Trevor Yeung, Xue Gong, Jenny Yuan, Julie Wilhelmy, Sylvie Robine, Laura D Attardi, Sylvia K Plevritis, Kenneth E Hung, Chang-Zheng Chen, Hanlee P Ji, Calvin J Kuo

一句话小结 ​

本研究利用未修改的单一气液界面培养方法，成功在小鼠模型中构建了多种胃肠道癌症的初级类器官，揭示了不同类型类器官对特定致癌突变的敏感性及其在癌症建模中的应用潜力，特别是结肠类器官在多重突变后重现结直肠癌的特征。研究表明，初级类器官系统不仅能够有效验证致癌基因的功能，还为理解癌症发展机制提供了重要工具，具有广泛的转化潜力。

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原代类器官 · 癌变 · 肠道组织 · 驱动癌基因 · 肿瘤模型

摘要 ​

将包含上皮和间充质成分的初级类器官培养应用于癌症建模，展现了将体内系统的准确多谱系分化和生理特性与转化细胞系的便捷体外操作相结合的潜力。在此，我们采用了一种未经过修改的单一气液界面培养方法，将致癌突变工程化导入来自小鼠结肠、胃和胰腺的初级上皮和间充质类器官。胰腺和胃类器官因表达携带G12D突变的Kras（Kras(G12D)）和p53缺失或两者同时导致发育不良，并在体内移植后容易产生腺癌。相比之下，初级结肠类器官在体外向侵袭性腺癌样组织的进展转化需要组合性Apc、p53、Kras(G12D)和Smad4突变，且在体内具备肿瘤发生性，重现了结直肠癌（CRC）的多重击模型，而小肠类器官的转化则相对更为随意。结肠类器官培养功能性验证了微RNA miR-483作为IGF2（类胰岛素生长因子-2）11p15.5 CRC扩增子上的主导驱动致癌基因，能够在体外诱导发育不良并在体内具备肿瘤发生性。这些研究展示了高度可操作的初级类器官系统在癌症建模和多样化胃肠组织中驱动致癌基因验证的普遍实用性。

英文摘要 ​

The application of primary organoid cultures containing epithelial and mesenchymal elements to cancer modeling holds promise for combining the accurate multilineage differentiation and physiology of in vivo systems with the facile in vitro manipulation of transformed cell lines. Here we used a single air-liquid interface culture method without modification to engineer oncogenic mutations into primary epithelial and mesenchymal organoids from mouse colon, stomach and pancreas. Pancreatic and gastric organoids exhibited dysplasia as a result of expression of Kras carrying the G12D mutation (Kras(G12D)), p53 loss or both and readily generated adenocarcinoma after in vivo transplantation. In contrast, primary colon organoids required combinatorial Apc, p53, Kras(G12D) and Smad4 mutations for progressive transformation to invasive adenocarcinoma-like histology in vitro and tumorigenicity in vivo, recapitulating multi-hit models of colorectal cancer (CRC), as compared to the more promiscuous transformation of small intestinal organoids. Colon organoid culture functionally validated the microRNA miR-483 as a dominant driver oncogene at the IGF2 (insulin-like growth factor-2) 11p15.5 CRC amplicon, inducing dysplasia in vitro and tumorigenicity in vivo. These studies demonstrate the general utility of a highly tractable primary organoid system for cancer modeling and driver oncogene validation in diverse gastrointestinal tissues.

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主要研究问题 ​

  1. 在不同的消化道组织中，原代类器官培养如何影响肿瘤发生机制的研究？
  2. 如何评估不同基因突变在消化道原代类器官中的肿瘤转化能力？
  3. 在原代类器官模型中，微小RNA如何调控肿瘤驱动基因的表达？
  4. 消化道原代类器官在癌症治疗研究中的潜在应用有哪些？
  5. 原代类器官文化的技术进步如何改变我们对消化道癌症的理解和研究方向？

核心洞察 ​

研究背景和目的 ​

本研究旨在开发一种基于原代器官培养的模型，以更好地模拟和研究多种消化系统肿瘤的发生机制。通过使用空气-液体界面培养技术，研究人员希望实现对小鼠胰腺、胃和结肠原代上皮及间质细胞的肿瘤转化，并探索癌基因的功能验证。

主要方法/材料/实验设计 ​

研究采用单一的空气-液体界面培养方法，能够在不添加外源生长因子的情况下培养含有上皮和间质成分的原代器官。具体流程如下：

Mermaid diagram
  1. 原代器官提取：从小鼠的胰腺、胃和结肠提取原代细胞。
  2. 空气-液体界面培养：将提取的细胞嵌入三维胶中进行培养。
  3. 癌基因感染：使用腺病毒感染原代器官以引入KrasG12D、p53缺失等癌基因。
  4. 组织学分析：通过H&E染色和免疫荧光标记评估细胞形态和增殖情况。
  5. 肿瘤转化验证：将转化的器官细胞移植到免疫缺陷小鼠中，观察肿瘤形成。

关键结果和发现 ​

  • 胰腺和胃的原代器官：在表达KrasG12D和/或p53缺失的情况下，原代器官能够展示明显的组织学异常和肿瘤形成。
  • 结肠原代器官：需要组合Apc、p53、KrasG12D和Smad4的突变才能实现侵袭性腺癌的转化，体现了结肠癌的多重突变模型。
  • miR-483的功能验证：在结肠癌相关的11p15.5扩增子中，miR-483被确认是一个主要的驱动癌基因，能够诱导细胞增殖和肿瘤形成。

主要结论/意义/创新性 ​

本研究展示了一种有效的原代器官培养方法，能够在体外模拟消化系统肿瘤的发生和发展，且不依赖于转化细胞系或外源生长因子。这一方法提供了一个生理相关的环境来研究肿瘤生物学和癌基因功能验证，可能推动癌症研究和治疗策略的开发。

研究局限性和未来方向 ​

  • 局限性：尽管本研究提供了强有力的模型，但仍需在其他类型的癌症和不同的动物模型中验证其适用性。
  • 未来方向：可以进一步探索原代器官模型在药物筛选和个性化治疗中的应用，以及如何利用间质成分来研究肿瘤微环境对癌症进展的影响。

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引用本文的文献 ​

  1. Biomimetic tissue-engineered systems for advancing cancer research: NCI Strategic Workshop report. - Teresa K Schuessler;Xin Yi Chan;Huanhuan Joyce Chen;Kyungmin Ji;Kyung Min Park;Alireza Roshan-Ghias;Pallavi Sethi;Archana Thakur;Xi Tian;Aranzazu Villasante;Ioannis K Zervantonakis;Nicole M Moore;Larry A Nagahara;Nastaran Z Kuhn - Cancer research (2014)
  2. One patient, two lesions, two oncogenic drivers of gastric cancer. - Clara Alsinet;Marco Ranzani;David J Adams - Genome biology (2014)
  3. Three-dimensional organotypic culture: experimental models of mammalian biology and disease. - Eliah R Shamir;Andrew J Ewald - Nature reviews. Molecular cell biology (2014)
  4. Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer. - Lincoln D Nadauld;Sarah Garcia;Georges Natsoulis;John M Bell;Laura Miotke;Erik S Hopmans;Hua Xu;Reetesh K Pai;Curt Palm;John F Regan;Hao Chen;Patrick Flaherty;Akifumi Ootani;Nancy R Zhang;James M Ford;Calvin J Kuo;Hanlee P Ji - Genome biology (2014)
  5. A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro. - Philipp Schlaermann;Benjamin Toelle;Hilmar Berger;Sven C Schmidt;Matthias Glanemann;Jürgen Ordemann;Sina Bartfeld;Hans J Mollenkopf;Thomas F Meyer - Gut (2016)
  6. Organoid models of human and mouse ductal pancreatic cancer. - Sylvia F Boj;Chang-Il Hwang;Lindsey A Baker;Iok In Christine Chio;Dannielle D Engle;Vincenzo Corbo;Myrthe Jager;Mariano Ponz-Sarvise;Hervé Tiriac;Mona S Spector;Ana Gracanin;Tobiloba Oni;Kenneth H Yu;Ruben van Boxtel;Meritxell Huch;Keith D Rivera;John P Wilson;Michael E Feigin;Daniel Öhlund;Abram Handly-Santana;Christine M Ardito-Abraham;Michael Ludwig;Ela Elyada;Brinda Alagesan;Giulia Biffi;Georgi N Yordanov;Bethany Delcuze;Brianna Creighton;Kevin Wright;Youngkyu Park;Folkert H M Morsink;I Quintus Molenaar;Inne H Borel Rinkes;Edwin Cuppen;Yuan Hao;Ying Jin;Isaac J Nijman;Christine Iacobuzio-Donahue;Steven D Leach;Darryl J Pappin;Molly Hammell;David S Klimstra;Olca Basturk;Ralph H Hruban;George Johan Offerhaus;Robert G J Vries;Hans Clevers;David A Tuveson - Cell (2015)
  7. Tissue-engineered models of human tumors for cancer research. - Aranzazu Villasante;Gordana Vunjak-Novakovic - Expert opinion on drug discovery (2015)
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