MaltSci 麦伴科研

Appearance

文献精选 > 高引权威"类器官"文献

Prospective derivation of a living organoid biobank of colorectal cancer patients. ​

文献信息 ​

PMID25957691
期刊Cell
影响因子42.5
JCR 分区Q1
发表年份2015
被引次数1252
关键词肠道癌, 类器官, 基因表达, 药物筛选
文献类型Journal Article, Research Support, Non-U.S. Gov't
ISSN0092-8674
页码933-45
期号161(4)
作者Marc van de Wetering, Hayley E Francies, Joshua M Francis, Gergana Bounova, Francesco Iorio, Apollo Pronk, Winan van Houdt, Joost van Gorp, Amaro Taylor-Weiner, Lennart Kester, Anne McLaren-Douglas, Joyce Blokker, Sridevi Jaksani, Sina Bartfeld, Richard Volckman, Peter van Sluis, Vivian S W Li, Sara Seepo, Chandra Sekhar Pedamallu, Kristian Cibulskis, Scott L Carter, Aaron McKenna, Michael S Lawrence, Lee Lichtenstein, Chip Stewart, Jan Koster, Rogier Versteeg, Alexander van Oudenaarden, Julio Saez-Rodriguez, Robert G J Vries, Gad Getz, Lodewyk Wessels, Michael R Stratton, Ultan McDermott, Matthew Meyerson, Mathew J Garnett, Hans Clevers

一句话小结 ​

本研究通过Rspondin基础的三维培养技术，从20例结直肠癌患者建立肿瘤类器官，发现这些类器官在遗传变化谱和基因表达上与原始肿瘤高度相似，具备高通量药物筛选潜力，能够揭示基因与药物反应的关系。该技术有望促进癌症遗传学与临床试验的结合，为个性化治疗提供新的思路和方法。

在麦伴科研 (maltsci.com) 搜索更多文献 ​

肠道癌 · 类器官 · 基因表达 · 药物筛选

摘要 ​

在Rspondin基础的三维培养中，来自多个器官的Lgr5干细胞形成不断扩展的上皮类器官，这些类器官保持其组织特性。我们报告了从20例连续结直肠癌（CRC）患者建立肿瘤类器官培养的情况。在大多数情况下，类器官也来自相邻的正常组织。类器官在多个方面与原始肿瘤密切相似。这个“活生物库”中的遗传变化谱与以前的结直肠癌大规模突变分析结果非常一致。基因表达分析表明，主要的结直肠癌分子亚型均有代表。肿瘤类器官适用于高通量药物筛选，能够检测基因与药物之间的关联。例如，单一类器官培养对Wnt分泌（刺猬）抑制剂表现出极高的敏感性，并且在负向Wnt反馈调节因子RNF43中带有突变，而不是在APC中。类器官技术可能弥补癌症遗传学与患者试验之间的差距，补充基于细胞系和异种移植的药物研究，并允许个性化治疗设计。

英文摘要 ​

In Rspondin-based 3D cultures, Lgr5 stem cells from multiple organs form ever-expanding epithelial organoids that retain their tissue identity. We report the establishment of tumor organoid cultures from 20 consecutive colorectal carcinoma (CRC) patients. For most, organoids were also generated from adjacent normal tissue. Organoids closely recapitulate several properties of the original tumor. The spectrum of genetic changes within the "living biobank" agrees well with previous large-scale mutational analyses of CRC. Gene expression analysis indicates that the major CRC molecular subtypes are represented. Tumor organoids are amenable to high-throughput drug screens allowing detection of gene-drug associations. As an example, a single organoid culture was exquisitely sensitive to Wnt secretion (porcupine) inhibitors and carried a mutation in the negative Wnt feedback regulator RNF43, rather than in APC. Organoid technology may fill the gap between cancer genetics and patient trials, complement cell-line- and xenograft-based drug studies, and allow personalized therapy design. PAPERCLIP.

麦伴智能科研服务 ​

智能阅读回答你对文献的任何问题，帮助理解文献中的复杂图表和公式
定位观点定位某个观点在文献中的蛛丝马迹
加入知识库完成数据提取，报告撰写等更多高级知识挖掘功能

主要研究问题 ​

  1. 如何评估肠道癌患者的肿瘤类器官与正常组织类器官在基因表达上的差异？
  2. 在建立活体类器官生物库的过程中，如何确保样本的代表性和多样性？
  3. 类器官技术在个性化治疗设计中，如何帮助识别不同肠道癌分子亚型的特征？
  4. 针对不同的肠道癌患者，类器官高通量药物筛选能否预测治疗反应的个体差异？
  5. 未来的研究中，如何利用肠道癌类器官进一步探索肿瘤微环境对癌症进展的影响？

核心洞察 ​

研究背景和目的 ​

随着生物医学技术的发展，肿瘤类器官（organoid）文化技术为癌症研究提供了新的平台。本文旨在建立来自结直肠癌（CRC）患者的肿瘤类器官文化，并评估其在药物筛选和个性化治疗中的应用潜力。

主要方法/材料/实验设计 ​

研究团队从20名连续结直肠癌患者获取样本，建立肿瘤类器官文化，并同时从相邻正常组织中提取类器官。研究主要采用以下步骤：

Mermaid diagram
  1. 患者样本收集：收集20名CRC患者的肿瘤及相邻正常组织样本。
  2. 肿瘤组织提取：从肿瘤组织中提取Lgr5干细胞，建立肿瘤类器官。
  3. 正常组织提取：从正常组织中提取相应的类器官。
  4. 基因组和转录组分析：分析类器官的基因组变化及基因表达情况。
  5. 药物筛选实验：进行高通量药物筛选，检测基因与药物的关联。

关键结果和发现 ​

  • 建立的肿瘤类器官成功保留了原始肿瘤的多种特性，与大规模突变分析结果一致。
  • 类器官中主要的CRC分子亚型得到了代表。
  • 某些肿瘤类器官对Wnt分泌抑制剂（porcupine抑制剂）表现出极高的敏感性，且相关类器官中发现了负向Wnt反馈调节因子RNF43的突变，而非APC。

主要结论/意义/创新性 ​

本文的研究结果表明，肿瘤类器官技术不仅能够有效地再现结直肠癌的遗传特征，还为药物筛选和个性化治疗提供了重要的实验平台。该技术填补了癌症遗传学与患者临床试验之间的空白，具有重要的临床应用前景。

研究局限性和未来方向 ​

  • 局限性：样本量相对较小，未来研究需扩大样本范围以提高结果的普适性。此外，肿瘤微环境的复杂性可能未能完全在类器官中重现。
  • 未来方向：建议未来研究可以结合更复杂的肿瘤微环境模型，以更全面地评估类器官在药物筛选和个性化治疗中的应用。同时，探索其他类型癌症的类器官文化技术也将是一个重要方向。

参考文献 ​

  1. Isolation of a novel human gene, APCDD1, as a direct target of the beta-Catenin/T-cell factor 4 complex with probable involvement in colorectal carcinogenesis. - Meiko Takahashi;Manabu Fujita;Yoichi Furukawa;Ryuji Hamamoto;Takashi Shimokawa;Nobutomo Miwa;Michio Ogawa;Yusuke Nakamura - Cancer research (2002)
  2. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. - Daniel Pinto;Alex Gregorieff;Harry Begthel;Hans Clevers - Genes & development (2003)
  3. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. - Frank Kuhnert;Corrine R Davis;Hsiao-Ting Wang;Pauline Chu;Mark Lee;Jenny Yuan;Roel Nusse;Calvin J Kuo - Proceedings of the National Academy of Sciences of the United States of America (2004)
  4. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. - Lyubomir T Vassilev;Binh T Vu;Bradford Graves;Daisy Carvajal;Frank Podlaski;Zoran Filipovic;Norman Kong;Ursula Kammlott;Christine Lukacs;Christian Klein;Nader Fotouhi;Emily A Liu - Science (New York, N.Y.) (2004)
  5. A census of human cancer genes. - P Andrew Futreal;Lachlan Coin;Mhairi Marshall;Thomas Down;Timothy Hubbard;Richard Wooster;Nazneen Rahman;Michael R Stratton - Nature reviews. Cancer (2004)
  6. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. - Anna-Pavlina G Haramis;Harry Begthel;Maaike van den Born;Johan van Es;Suzanne Jonkheer;G Johan A Offerhaus;Hans Clevers - Science (New York, N.Y.) (2004)
  7. Mitogenic influence of human R-spondin1 on the intestinal epithelium. - Kyung-Ah Kim;Makoto Kakitani;Jingsong Zhao;Takeshi Oshima;Tom Tang;Minke Binnerts;Yi Liu;Bryan Boyle;Emily Park;Peter Emtage;Walter D Funk;Kazuma Tomizuka - Science (New York, N.Y.) (2005)
  8. Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells. - I Ivanov;K C Lo;L Hawthorn;J K Cowell;Y Ionov - Oncogene (2007)
  9. Identification of stem cells in small intestine and colon by marker gene Lgr5. - Nick Barker;Johan H van Es;Jeroen Kuipers;Pekka Kujala;Maaike van den Born;Miranda Cozijnsen;Andrea Haegebarth;Jeroen Korving;Harry Begthel;Peter J Peters;Hans Clevers - Nature (2007)
  10. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. - Federica Di Nicolantonio;Miriam Martini;Francesca Molinari;Andrea Sartore-Bianchi;Sabrina Arena;Piercarlo Saletti;Sara De Dosso;Luca Mazzucchelli;Milo Frattini;Salvatore Siena;Alberto Bardelli - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2008)

引用本文的文献 ​

  1. Sequential cancer mutations in cultured human intestinal stem cells. - Jarno Drost;Richard H van Jaarsveld;Bas Ponsioen;Cheryl Zimberlin;Ruben van Boxtel;Arjan Buijs;Norman Sachs;René M Overmeer;G Johan Offerhaus;Harry Begthel;Jeroen Korving;Marc van de Wetering;Gerald Schwank;Meike Logtenberg;Edwin Cuppen;Hugo J Snippert;Jan Paul Medema;Geert J P L Kops;Hans Clevers - Nature (2015)
  2. An ecosystem of cancer cell line factories to support a cancer dependency map. - Jesse S Boehm;Todd R Golub - Nature reviews. Genetics (2015)
  3. Development and application of human adult stem or progenitor cell organoids. - Maarten B Rookmaaker;Frans Schutgens;Marianne C Verhaar;Hans Clevers - Nature reviews. Nephrology (2015)
  4. The boom in mini stomachs, brains, breasts, kidneys and more. - Cassandra Willyard - Nature (2015)
  5. Colorectal cancer models for novel drug discovery. - Daniel Golovko;Dmitriy Kedrin;Ömer H Yilmaz;Jatin Roper - Expert opinion on drug discovery (2015)
  6. Can kinomics and proteomics bridge the gap between pediatric cancers and newly designed kinase inhibitors? - Naomi E van der Sligte;Kim R Kampen;Eveline S J M de Bont - Cellular and molecular life sciences : CMLS (2015)
  7. Programmed synthesis of three-dimensional tissues. - Michael E Todhunter;Noel Y Jee;Alex J Hughes;Maxwell C Coyle;Alec Cerchiari;Justin Farlow;James C Garbe;Mark A LaBarge;Tejal A Desai;Zev J Gartner - Nature methods (2015)
  8. Mouse models of intestinal cancer. - Rene Jackstadt;Owen J Sansom - The Journal of pathology (2016)
  9. Preclinical models of pancreatic ductal adenocarcinoma. - Chang-Il Hwang;Sylvia F Boj;Hans Clevers;David A Tuveson - The Journal of pathology (2016)
  10. Cell hierarchies in colorectal cancer: focus on APC and BRAF. - Markus Morkel;Pamela Riemer - Oncoscience (2015)

... (1242 更多 篇文献)

© 2025 MaltSci 麦伴科研 - 我们用人工智能技术重塑科研