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Gut. 2019 Feb;68(2):207-217. doi: 10.1136/gutjnl-2017-314549. Epub 2018 Apr 27.

Human gastric cancer modelling using organoids.

Author information

1
Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
2
Core Unit for Molecular Tumour Diagnostics (CMTD), National Center for Tumour Diseases (NCT) Dresden, Dresden, Germany.
3
Department 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
Partner Site Dresden, German Cancer Consortium (DKTK), Heidelberg, Germany.
5
Institute 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
Partner Site Dresden, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
7
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
8
Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
#
Contributed equally

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.

KEYWORDS:

gastric cancer

PMID:
29703791
DOI:
10.1136/gutjnl-2017-314549
[Indexed for MEDLINE]
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