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Original article
Human gastric cancer modelling using organoids
  1. Therese Seidlitz1,
  2. Sebastian R Merker1,
  3. Alexander Rothe1,
  4. Falk Zakrzewski2,
  5. Cläre von Neubeck3,4,
  6. Konrad Grützmann2,
  7. Ulrich Sommer5,
  8. Christine Schweitzer1,
  9. Sebastian Schölch1,4,6,
  10. Heike Uhlemann1,
  11. Anne-Marlene Gaebler1,
  12. Kristin Werner1,
  13. Mechthild Krause3,4,6,
  14. Gustavo B Baretton2,5,
  15. Thilo Welsch1,4,6,
  16. Bon-Kyoung Koo7,
  17. Daniela E Aust2,5,
  18. Barbara Klink2,4,6,8,
  19. Jürgen Weitz1,4,6,
  20. Daniel E Stange1,4,6
  1. 1Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany
  2. 2Core Unit for Molecular Tumour Diagnostics (CMTD), National Center for Tumour Diseases (NCT) Dresden, Dresden, Germany
  3. 3Department of Radiotherapy and Radiation Oncology and National Center for Radiation Research in Oncology (OncoRay), University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany
  4. 4Partner Site Dresden, German Cancer Consortium (DKTK), Heidelberg, Germany
  5. 5Institute for Pathology and Tumour and Normal Tissue Bank of the University Cancer Center (UCC), University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany
  6. 6Partner Site Dresden, National Center for Tumor Diseases (NCT), Heidelberg, Germany
  7. 7Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
  8. 8Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany
  1. Correspondence to Dr Daniel E Stange, Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany; daniel.stange{at}uniklinikum-dresden.de

Abstract

Objective Gastric cancer is the second leading cause of cancer-related deaths and the fifth most common malignancy worldwide. In this study, human and mouse gastric cancer organoids were generated to model the disease and perform drug testing to delineate treatment strategies.

Design Human gastric cancer organoid cultures were established, samples classified according to their molecular profile and their response to conventional chemotherapeutics tested. Targeted treatment was performed according to specific druggable mutations. Mouse gastric cancer organoid cultures were generated carrying molecular subtype-specific alterations.

Results Twenty human gastric cancer organoid cultures were established and four selected for a comprehensive in-depth analysis. Organoids demonstrated divergent growth characteristics and morphologies. Immunohistochemistry showed similar characteristics to the corresponding primary tissue. A divergent response to 5-fluoruracil, oxaliplatin, irinotecan, epirubicin and docetaxel treatment was observed. Whole genome sequencing revealed a mutational spectrum that corresponded to the previously identified microsatellite instable, genomic stable and chromosomal instable subtypes of gastric cancer. The mutational landscape allowed targeted therapy with trastuzumab for ERBB2 alterations and palbociclib for CDKN2A loss. Mouse cancer organoids carrying Kras and Tp53 or Apc and Cdh1 mutations were characterised and serve as model system to study the signalling of induced pathways.

Conclusion We generated human and mouse gastric cancer organoids modelling typical characteristics and altered pathways of human gastric cancer. Successful interference with activated pathways demonstrates their potential usefulness as living biomarkers for therapy response testing.

  • gastric cancer

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Footnotes

  • TS, SRM and AR contributed equally.

  • Contributors Study concept and design: TS, SRM, DES. Acquisition of data: TS, SRM, FZ, CvN, AR, KG, CS, SS, KW, HU, US, DEA, BK. Analysis and interpretation of data: all coauthors. Drafting of the manuscript: TS, SRM, DES. Critical revision of the manuscript for important intellectual content: GBB, TW, DEA, MK, JW. Statistical analysis: TS, SRM, FZ, KG, BK.

  • Funding Funding was provided by the Deutsche Krebshilfe (No 111350), the Sander Stiftung (No 2014.104.1), the Hector Stiftung (No M65.2) and the European Union (ERC No 639050) to DES. AR was supported by the Preiss-Daimler Stiftung and Medizinischen Fakultät Carl Gustav Carus TU Dresden. AMG was supported by the Deutsche Krebshilfe (No 70112925).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Ethical Committee of the TU Dresden (No EK451122014).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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