TY - JOUR
T1 - Human gastric cancer modelling using organoids
AU - Seidlitz, Therese
AU - Merker, Sebastian R.
AU - Rothe, Alexander
AU - Zakrzewski, Falk
AU - Von Neubeck, Cläre
AU - Grützmann, Konrad
AU - Sommer, Ulrich
AU - Schweitzer, Christine
AU - Schölch, Sebastian
AU - Uhlemann, Heike
AU - Gaebler, Anne Marlene
AU - Werner, Kristin
AU - Krause, Mechthild
AU - Baretton, Gustavo B.
AU - Welsch, Thilo
AU - Koo, Bon Kyoung
AU - Aust, Daniela E.
AU - Klink, Barbara
AU - Weitz, Jürgen
AU - Stange, Daniel E.
N1 - Publisher Copyright:
© 2019 Article author(s). All rights reserved.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85049142911&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2017-314549
DO - 10.1136/gutjnl-2017-314549
M3 - Article
C2 - 29703791
AN - SCOPUS:85049142911
SN - 0017-5749
VL - 68
SP - 207
EP - 217
JO - Gut
JF - Gut
IS - 2
ER -