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Organoid models of human and mouse ductal pancreatic cancer. ​

文献信息 ​

PMID25557080
期刊Cell
影响因子42.5
JCR 分区Q1
发表年份2015
被引次数1183
关键词胰腺癌, 类器官模型, 肿瘤发生, 转录组分析, 蛋白质组分析
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0092-8674
页码324-38
期号160(1-2)
作者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

一句话小结 ​

本研究建立了一种来自正常和肿瘤胰腺组织的类器官模型，以便于研究胰腺癌的发生机制，发现了与疾病进展相关的基因和通路。该模型不仅能够重现肿瘤发展的全过程，还为进一步的基因操作提供了平台，显示出其在胰腺癌研究中的重要应用潜力。

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胰腺癌 · 类器官模型 · 肿瘤发生 · 转录组分析 · 蛋白质组分析

摘要 ​

胰腺癌是最致命的恶性肿瘤之一，主要由于其晚期诊断和对治疗的有限反应。因此，迫切需要可行的方法来识别和研究与胰腺肿瘤发生相关的途径。我们建立了来自正常和肿瘤小鼠及人类胰腺组织的类器官模型。胰腺类器官可以迅速从切除的肿瘤和活检中生成，能够耐受冷冻保存，并表现出特定于导管和疾病阶段的特征。正位移植的肿瘤类器官重现了肿瘤发展的全过程，从形成早期等级的肿瘤到发展为局部侵袭性和转移性癌症。由于能够进行基因操作，类器官成为探究基因合作的平台。对小鼠胰腺类器官进行的全面转录组和蛋白质组分析揭示了在疾病进展过程中发生改变的基因和途径。在人类组织中确认了许多这些蛋白质变化，证明类器官是一种便捷的模型系统，用于发现这一致命恶性肿瘤的特征。

英文摘要 ​

Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

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主要研究问题 ​

  1. 除了基因操作外，类器官模型在研究胰腺癌的其他应用有哪些？
  2. 这些类器官模型如何帮助我们理解胰腺癌的微环境及其对肿瘤发展的影响？
  3. 在胰腺癌的研究中，类器官模型与传统细胞培养或动物模型相比，有哪些优势和局限性？
  4. 类器官模型的建立过程中，选择正常与肿瘤组织样本对结果有何影响？
  5. 如何利用类器官模型筛选新型药物或治疗方案，以改善胰腺癌患者的预后？

核心洞察 ​

研究背景和目的 ​

胰腺癌是最致命的恶性肿瘤之一，因其晚期诊断和对治疗的有限反应而受到广泛关注。因此，急需有效的方法来识别和探讨胰腺肿瘤发生的相关通路。本研究旨在建立可用于研究胰腺癌的类器官模型，以便深入了解肿瘤的生物学特性和潜在的治疗靶点。

主要方法/材料/实验设计 ​

本研究采用了从正常和肿瘤性小鼠及人类胰腺组织中建立类器官模型的方法。具体步骤如下：

Mermaid diagram
  • 胰腺组织采集：从手术切除的肿瘤和活检样本中获取胰腺组织。
  • 建立类器官模型：利用培养技术快速生成胰腺类器官，能够在低温保存条件下存活。
  • 类器官的特性分析：观察类器官的管腔特征和疾病阶段特征。
  • 转基因操作：对类器官进行基因操控，以探讨基因间的相互作用。
  • 转录组和蛋白组分析：对小鼠胰腺类器官进行全面的转录组和蛋白组分析，以识别在疾病进展中改变的基因和通路。
  • 临床样本验证：确认在临床样本中许多蛋白变化的存在，证明类器官模型的有效性。
  • 数据整合与解读：综合分析实验数据，以揭示胰腺癌的生物特征。

关键结果和发现 ​

  • 成功建立了来自正常和肿瘤胰腺的类器官模型，这些模型能够重现胰腺癌的多种特征。
  • 类器官能够形成早期级别的肿瘤，随后进展为局部侵袭性和转移性癌症。
  • 转录组和蛋白组分析揭示了与疾病进展相关的多条基因和通路。
  • 在人类组织中确认了许多与小鼠类器官中发现的蛋白质变化相一致的结果。

主要结论/意义/创新性 ​

本研究表明，胰腺类器官模型是研究胰腺癌的有效工具，能够提供关于肿瘤发生和发展的重要信息。这些类器官不仅可以用于探索肿瘤生物学，还可以作为测试新疗法的模型，为胰腺癌的早期诊断和治疗提供新的思路。

研究局限性和未来方向 ​

  • 局限性：当前研究主要基于小鼠模型，未来需要更多的人类临床样本来验证发现的普适性。
  • 未来方向：进一步探讨类器官模型在药物筛选和个体化治疗中的应用，探索与其他类型癌症的比较研究，以及利用基因编辑技术深入分析肿瘤的分子机制。

参考文献 ​

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  5. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. - Nick Barker;Meritxell Huch;Pekka Kujala;Marc van de Wetering;Hugo J Snippert;Johan H van Es;Toshiro Sato;Daniel E Stange;Harry Begthel;Maaike van den Born;Esther Danenberg;Stieneke van den Brink;Jeroen Korving;Arie Abo;Peter J Peters;Nick Wright;Richard Poulsom;Hans Clevers - Cell stem cell (2010)
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  7. Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. - Sreenath V Sharma;Daniel A Haber;Jeff Settleman - Nature reviews. Cancer (2010)
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引用本文的文献 ​

  1. Pancreatic cancer: From normal to metastases--a whole gamut of pancreatic organoids. - Gillian Patman - Nature reviews. Gastroenterology & hepatology (2015)
  2. Toward recreating colon cancer in human organoids. - Ameen A Salahudeen;Calvin J Kuo - Nature medicine (2015)
  3. Organoid development in cancer genome discovery. - Dong Gao;Yu Chen - Current opinion in genetics & development (2015)
  4. Imaging tumor metabolism using positron emission tomography. - David Y Lewis;Dmitry Soloviev;Kevin M Brindle - Cancer journal (Sudbury, Mass.) (2015)
  5. Organoid modeling for cancer precision medicine. - Michael A Cantrell;Calvin J Kuo - Genome medicine (2015)
  6. Examining the utility of patient-derived xenograft mouse models. - Samuel Aparicio;Manuel Hidalgo;Andrew L Kung - Nature reviews. Cancer (2015)
  7. Translational value of mouse models in oncology drug development. - Stephen E Gould;Melissa R Junttila;Frederic J de Sauvage - Nature medicine (2015)
  8. Advances and applications of single-cell sequencing technologies. - Yong Wang;Nicholas E Navin - Molecular cell (2015)
  9. MYC in pancreatic cancer: novel mechanistic insights and their translation into therapeutic strategies. - E Hessmann;G Schneider;V Ellenrieder;J T Siveke - Oncogene (2016)
  10. The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. - Nathan M Krah;Jean-Paul De La O;Galvin H Swift;Chinh Q Hoang;Spencer G Willet;Fong Chen Pan;Gabriela M Cash;Mary P Bronner;Christopher Ve Wright;Raymond J MacDonald;L Charles Murtaugh - eLife (2015)

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