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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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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