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

Literature Information ​

PMID25957691
JournalCell
Impact Factor42.5
JCR QuartileQ1
Publication Year2015
Times Cited1252
Keywordscolorectal cancer, organoids, biobank, gene expression, personalized therapy
Literature TypeJournal Article, Research Support, Non-U.S. Gov't
ISSN0092-8674
Pages933-45
Issue161(4)
AuthorsMarc 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

TL;DR ​

This study establishes tumor organoid cultures from colorectal carcinoma patients, demonstrating that these organoids retain key characteristics of the original tumors and reflect their genetic diversity, which aligns with established mutational analyses. The research highlights the potential of organoid technology for high-throughput drug screening and personalized therapy design, bridging the gap between cancer genetics and clinical applications.

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colorectal cancer · organoids · biobank · gene expression · personalized therapy

Abstract ​

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.

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Primary Questions Addressed ​

  1. How can the establishment of a living organoid biobank enhance our understanding of the heterogeneity in colorectal cancer?
  2. What are the potential implications of using organoid cultures for personalized therapy in colorectal cancer patients?
  3. In what ways do the genetic profiles of organoids correlate with patient outcomes in colorectal cancer treatment?
  4. How might the use of organoid technology change the approach to drug discovery and development in oncology?
  5. What challenges are associated with maintaining the long-term viability and fidelity of organoid cultures derived from colorectal cancer patients?

Key Findings ​

Research Background and Objectives ​

Colorectal carcinoma (CRC) is a prevalent cancer type characterized by diverse genetic mutations and varying responses to treatment. The objective of this study was to establish tumor organoid cultures from CRC patients, which could serve as a living biobank for understanding tumor biology, drug response, and personalized therapy development.

Main Methods/Materials/Experimental Design ​

The study employed Rspondin-based 3D cultures to derive organoids from Lgr5 stem cells harvested from tumor tissues of 20 consecutive CRC patients, along with adjacent normal tissues when possible. The organoids were analyzed for genetic mutations and gene expression profiles.

Mermaid diagram

Key Results and Findings ​

  • Organoid Viability: The established organoids retained characteristics of the original tumors, including histological features and genetic mutations.
  • Genetic Changes: The organoids reflected a spectrum of genetic alterations consistent with previous studies on CRC, reinforcing their validity as a model.
  • Molecular Subtypes: Gene expression profiling indicated that major CRC molecular subtypes were adequately represented in the organoid cultures.
  • Drug Screening: High-throughput screening revealed specific drug sensitivities, including a notable response to Wnt secretion inhibitors in a particular organoid that had a mutation in RNF43.

Main Conclusions/Significance/Innovation ​

The study demonstrates that organoid technology can effectively bridge the gap between cancer genetics and clinical application. The organoids not only mirror the original tumor's biology but also allow for personalized medicine approaches through drug screening. This innovation provides a platform for more tailored therapies and enhances the understanding of CRC heterogeneity.

Research Limitations and Future Directions ​

  • Limitations: The study was limited to a relatively small cohort of 20 patients, which may not fully represent the diversity of CRC. Additionally, the long-term viability and stability of organoids need further investigation.
  • Future Directions: Expanding the patient cohort and incorporating organoids from other cancer types could enhance the utility of this approach. Further research is needed to refine drug screening processes and validate the predictive power of organoid responses in clinical settings.

References ​

  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)

Literatures Citing This Work ​

  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 more literatures)

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