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Published on: August 25, 2015
Mouse Models of Human Gastric Cancer Subtypes With Stomach-Specific CreERT2-Mediated Pathway Alterations
Therese Seidlitz1, Yi-Ting Chen2, Heike Uhlemann1
1Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Background & Aims:
Patterns of genetic alterations characterize different molecular subtypes of human gastric cancer. We aimed to establish mouse models of these subtypes.
Methods:
We searched databases to identify genes with unique expression in the stomach epithelium, resulting in the identification of Anxa10. We generated mice with tamoxifen-inducible Cre recombinase (CreERT2) in the Anxa10 gene locus. We created 3 mouse models with alterations in pathways that characterize the chromosomal instability (CIN) and the genomically stable (GS) subtypes of human gastric cancer: Anxa10-CreERT2;KrasG12D/+;Tp53R172H/+;Smad4fl/f (CIN mice), Anxa10-CreERT2;Cdh1fl/fl;KrasG12D/+;Smad4fl/fl (GS-TGBF mice), and Anxa10-CreERT2;Cdh1fl/fl;KrasG12D/+;Apcfl/fl (GS-Wnt mice). We analyzed tumors that developed in these mice by histology for cell types and metastatic potential. We derived organoids from the tumors and tested their response to chemotherapeutic agents and the epithelial growth factor receptor signaling pathway inhibitor trametinib.
Results:
The gastric tumors from the CIN mice had an invasive phenotype and formed liver and lung metastases. The tumor cells had a glandular morphology, similar to human intestinal-type gastric cancer. The gastric tumors from the GS-TGFB mice were poorly differentiated with diffuse morphology and signet ring cells, resembling human diffuse-type gastric cancer. Cells from these tumors were invasive, and mice developed peritoneal carcinomatosis and lung metastases. GS-Wnt mice developed adenomatous tooth-like gastric cancer. Organoids derived from tumors of GS-TGBF and GS-Wnt mice were more resistant to docetaxel, whereas organoids from the CIN tumors were more resistant to trametinib.
Conclusions:
Using a stomach-specific CreERT2 system, we created mice that develop tumors with morphologic similarities to subtypes of human gastric cancer. These tumors have different patterns of local growth, metastasis, and response to therapeutic agents. They can be used to study different subtypes of human gastric cancer.
Insights
Researchers developed novel mouse models for human gastric cancer subtypes by targeting the Anxa10 gene. These models mimic distinct human gastric cancer types and show varied responses to therapies, aiding future research.
Area of Science:
- Oncology
- Genetics
- Animal Models
Background:
- Genetic alterations define human gastric cancer molecular subtypes.
- Developing accurate mouse models for these subtypes is crucial for research.
Purpose of the Study:
- To create mouse models that recapitulate the molecular subtypes of human gastric cancer.
- To investigate the characteristics and therapeutic responses of these models.
Main Methods:
- Identified Anxa10 as a stomach-specific gene for targeting.
- Generated tamoxifen-inducible Cre recombinase (CreERT2) mice in the Anxa10 locus.
- Created three distinct mouse models representing chromosomal instability (CIN) and genomically stable (GS) gastric cancer subtypes, incorporating key genetic alterations.
Main Results:
- CIN mouse models developed invasive tumors with liver and lung metastases, resembling intestinal-type gastric cancer.
- GS-TGFB mouse models exhibited poorly differentiated, diffuse tumors with signet ring cells, similar to diffuse-type gastric cancer, and showed peritoneal carcinomatosis and lung metastases.
- GS-Wnt mouse models developed adenomatous tooth-like gastric cancer.
- Organoids from GS-TGFB and GS-Wnt models showed resistance to docetaxel, while CIN organoids were resistant to trametinib.
Conclusions:
- Developed stomach-specific CreERT2 mouse models for gastric cancer subtypes.
- These models display distinct tumor morphology, metastatic potential, and therapeutic responses.
- The models serve as valuable tools for studying human gastric cancer subtypes.
