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

Literature Information ​

DOI10.1038/nm.3585
PMID24859528
JournalNature medicine
Impact Factor50.0
JCR QuartileQ1
Publication Year2014
Times Cited257
Keywordsprimary organoids, oncogenic transformation, gastrointestinal tissues, cancer modeling, driver oncogene
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN1078-8956
Pages769-77
Issue20(7)
AuthorsXingnan 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

TL;DR ​

This study explores the use of primary organoid cultures from mouse colon, stomach, and pancreas to model cancer, revealing that pancreatic and gastric organoids develop dysplasia and adenocarcinoma with specific mutations, while colon organoids require multiple mutations for transformation, reflecting colorectal cancer progression. The findings highlight the effectiveness of primary organoid systems in validating driver oncogenes like miR-483 and provide insights into gastrointestinal cancer modeling.

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primary organoids · oncogenic transformation · gastrointestinal tissues · cancer modeling · driver oncogene

Abstract ​

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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Primary Questions Addressed ​

  1. How do the oncogenic mutations in pancreatic and gastric organoids differ in their pathways to tumorigenesis compared to colon organoids?
  2. What are the implications of using primary organoid cultures for studying the multi-hit models of colorectal cancer in comparison to traditional cell lines?
  3. How might the findings regarding miR-483 as a driver oncogene influence future therapeutic strategies for colorectal cancer?
  4. In what ways can the single air-liquid interface culture method be optimized to enhance the study of oncogenic transformations in other gastrointestinal tissues?
  5. What are the potential limitations of using primary organoid cultures in cancer modeling, particularly in terms of replicating the tumor microenvironment?

Key Findings ​

Research Background and Purpose ​

The study focuses on the application of primary organoid cultures derived from various gastrointestinal tissues to model cancer, specifically pancreatic, gastric, and colorectal cancers. The objective is to demonstrate how a single air-liquid interface culture method can effectively engineer oncogenic mutations in these organoids, providing a robust platform for studying tumorigenesis and validating potential oncogenes.

Main Methods/Materials/Experimental Design ​

The researchers utilized a primary organoid culture system that maintains both epithelial and mesenchymal components from mouse colon, stomach, and pancreas. The air-liquid interface method was employed without the need for exogenous growth factors, allowing for sustained growth and differentiation of organoids.

Experimental Workflow ​

Mermaid diagram
  1. Primary Tissue Collection: Tissues from mouse models were dissected and prepared for organoid culture.
  2. Organoid Culture: Organoids were established using an air-liquid interface method, supporting long-term growth.
  3. Oncogenic Mutation Engineering: Mutations in genes such as Kras, p53, Apc, and Smad4 were introduced to study their roles in cancer progression.
  4. In Vitro Transformation Assessment: Histological changes were monitored to evaluate the degree of dysplasia and transformation.
  5. In Vivo Tumorigenicity Testing: Transplanted organoids were assessed for tumor formation in immunocompromised mice.
  6. Driver Oncogene Validation: The study validated the role of specific oncogenes, particularly miR-483, in cancer development.

Key Results and Findings ​

  • Pancreatic and Gastric Organoids: The introduction of KrasG12D and p53 mutations resulted in dysplasia and the formation of adenocarcinomas upon in vivo transplantation.
  • Colon Organoids: Required a combination of mutations (Apc, p53, KrasG12D, and Smad4) for the progression to invasive adenocarcinoma-like histology.
  • Driver Oncogene Validation: miR-483 was identified as a dominant driver oncogene in the IGF2 amplicon associated with colorectal cancer, showing significant induction of dysplasia and tumorigenicity in organoids.

Main Conclusions/Significance/Innovation ​

The study establishes a versatile and effective primary organoid culture system for modeling gastrointestinal cancers. This method not only allows for the accurate representation of tumorigenesis but also facilitates the functional validation of potential oncogenes in a physiologically relevant context. The findings highlight the utility of organoid systems in cancer research, paving the way for future applications in therapeutic development and oncogene discovery.

Research Limitations and Future Directions ​

  • Limitations: The study primarily utilized mouse models, which may not fully recapitulate human cancer biology. Additionally, the focus on specific mutations may overlook other relevant genetic alterations in cancer.
  • Future Directions: Future research could explore the application of this organoid system to human tissues and incorporate additional genetic variations to model a broader spectrum of cancer phenotypes. Further investigation into the role of the tumor microenvironment and stroma in cancer progression using organoid models is also warranted.

References ​

  1. A new link between epigenetic progenitor lesions in cancer and the dynamics of signal transduction. - Winston Timp;Andre Levchenko;Andrew P Feinberg - Cell cycle (Georgetown, Tex.) (2009)
  2. Colony-forming cells in the adult mouse pancreas are expandable in Matrigel and form endocrine/acinar colonies in laminin hydrogel. - Liang Jin;Tao Feng;Hung Ping Shih;Ricardo Zerda;Angela Luo;Jasper Hsu;Alborz Mahdavi;Maike Sander;David A Tirrell;Arthur D Riggs;Hsun Teresa Ku - Proceedings of the National Academy of Sciences of the United States of America (2013)
  3. Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis. - H Nikki March;Alistair G Rust;Nicholas A Wright;Jelle ten Hoeve;Jeroen de Ridder;Matthew Eldridge;Louise van der Weyden;Anton Berns;Jules Gadiot;Anthony Uren;Richard Kemp;Mark J Arends;Lodewyk F A Wessels;Douglas J Winton;David J Adams - Nature genetics (2011)
  4. Establishment of a long-term three-dimensional primary culture of mouse glandular stomach epithelial cells within the stem cell niche. - Takahito Katano;Akifumi Ootani;Tsutomu Mizoshita;Satoshi Tanida;Hironobu Tsukamoto;Keiji Ozeki;Masahide Ebi;Yoshinori Mori;Hiromi Kataoka;Takeshi Kamiya;Shuji Toda;Takashi Joh - Biochemical and biophysical research communications (2013)
  5. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. - Fatima el Marjou;Klaus-Peter Janssen;Benny Hung-Junn Chang;Mei Li;Valérie Hindie;Lawrence Chan;Daniel Louvard;Pierre Chambon;Daniel Metzger;Sylvie Robine - Genesis (New York, N.Y. : 2000) (2004)
  6. Oncogene-mediated human lung epithelial cell transformation produces adenocarcinoma phenotypes in vivo. - Ken Sasai;Taiko Sukezane;Emmy Yanagita;Harumi Nakagawa;Azusa Hotta;Tomoo Itoh;Tsuyoshi Akagi - Cancer research (2011)
  7. Control of beta-cell differentiation by the pancreatic mesenchyme. - Myriam Attali;Volodymyr Stetsyuk;Annie Basmaciogullari;Virginie Aiello;Maria A Zanta-Boussif;Bertrand Duvillie;Raphael Scharfmann - Diabetes (2007)
  8. Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. - Ross A Dickins;Michael T Hemann;Jack T Zilfou;David R Simpson;Ingrid Ibarra;Gregory J Hannon;Scott W Lowe - Nature genetics (2005)
  9. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. - Toshiro Sato;Hans Clevers - Science (New York, N.Y.) (2013)
  10. Comprehensive molecular characterization of human colon and rectal cancer. - - Nature (2012)

Literatures Citing This Work ​

  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)
  8. Reprogramming of human cancer cells to pluripotency for models of cancer progression. - Jungsun Kim;Kenneth S Zaret - The EMBO journal (2015)
  9. Toward recreating colon cancer in human organoids. - Ameen A Salahudeen;Calvin J Kuo - Nature medicine (2015)
  10. Generating human intestinal tissues from pluripotent stem cells to study development and disease. - Katie L Sinagoga;James M Wells - The EMBO journal (2015)

... (247 more literatures)

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