Human gastric cancer modelling using organoids

被引：232

作者：

Seidlitz, Therese ^{[1
]}

Merker, Sebastian R. ^{[1
]}

Rothe, Alexander ^{[1
]}

Zakrzewski, Falk ^{[2
]}

von Neubeck, Claere ^{[3
,4
,5
]}

Gruetzmann, Konrad ^{[2
]}

Sommer, Ulrich ^{[6
,7
]}

Schweitzer, Christine ^{[1
]}

Schoelch, Sebastian ^{[1
,5
,8
]}

Uhlemann, Heike ^{[1
]}

Gaebler, Anne-Marlene ^{[1
]}

Werner, Kristin ^{[1
]}

Krause, Mechthild ^{[3
,4
,5
,8
]}

Baretton, Gustavo B. ^{[2
,6
,7
]}

Welsch, Thilo ^{[1
,5
,8
]}

Koo, Bon-Kyoung ^{[9
]}

Aust, Daniela E. ^{[2
,6
,7
]}

Klink, Barbara ^{[2
,5
,8
,10
]}

Weitz, Juergen ^{[1
,5
,8
]}

Stange, Daniel E. ^{[1
,5
,8
]}

机构：

[1] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Med Fac, Dept Visceral Thorac & Vasc Surg, D-01307 Dresden, Germany

[2] Natl Ctr Tumour Dis NCT Dresden, Core Unit Mol Tumour Diagnost CMTD, Dresden, Germany

[3] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Med Fac, Dept Radiotherapy & Radiat Oncol, Dresden, Germany

[4] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Med Fac, Natl Ctr Radiat Res Oncol OncoRay, Dresden, Germany

[5] German Canc Consortium DKTK, Partner Site Dresden, Heidelberg, Germany

[6] Tech Univ Dresden, UCC, Univ Hosp Carl Gustav Carus, Inst Pathol,Med Fac, Dresden, Germany

[7] Tech Univ Dresden, UCC, Univ Hosp Carl Gustav Carus, Tumour & Normal Tissue Bank,Med Fac, Dresden, Germany

[8] Natl Ctr Tumor Dis NCT, Partner Site Dresden, Heidelberg, Germany

[9] Austrian Acad Sci IMBA, Inst Mol Biotechnol, Vienna, Austria

[10] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Inst Clin Genet, Med Fac, Dresden, Germany

来源：

GUT | 2019年 / 68卷 / 02期

基金：

欧洲研究理事会; 芬兰科学院;

关键词：

STEM-CELLS; PERIOPERATIVE CHEMOTHERAPY; IN-VITRO; ADENOCARCINOMA; STOMACH; TARGETS; IDENTIFICATION; MULTICENTER; EXPRESSION; EXPANSION;

D O I：

10.1136/gutjnl-2017-314549

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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. 3 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.

引用

页码：207 / 217

页数：11

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