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Updated: Jul 15, 2025
Orthotopic Mouse Model of Colorectal Cancer
Published on: December 4, 2007
Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer
Yurong Song1, Travis D Kerr1, Chelsea Sanders2
1Frederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United States.
Background:
Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, and PMS2) play a critical role in the DNA damage response pathway for genome integrity maintenance. Germline mutations of MMR genes can lead to Lynch syndrome or constitutional mismatch repair deficiency syndrome, resulting in an increased lifetime risk of developing cancer characterized by high microsatellite instability (MSI-H) and high mutation burden. Although immunotherapy has been approved for MMR-deficient (MMRd) cancer patients, the overall response rate needs to be improved and other management options are needed.
Methods:
To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization.
Results:
The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node.
Conclusions:
The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.
Insights
Researchers developed organoids and mouse models from DNA mismatch repair-deficient (MMRd) cancers. These models mimic high microsatellite instability (MSI-H) and metastasis, aiding the study of MMRd cancer biology and treatment development.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Genome integrity is vital for organism survival, with DNA mismatch repair (MMR) genes crucial for DNA damage response.
- Germline mutations in MMR genes cause Lynch syndrome or constitutional mismatch repair deficiency syndrome, increasing cancer risk with high microsatellite instability (MSI-H).
- While immunotherapy is approved for MMR-deficient (MMRd) cancers, improved response rates and management strategies are needed.
Purpose of the Study:
- To investigate MMRd cancer biology.
- To understand resistance mechanisms to immune modulation.
- To develop vaccines and therapeutic testing platforms for MMRd cancers.
Main Methods:
- Generated organoids and an orthotopic mouse model from intestine tumors in Msh2-deficient mice.
- Characterized organoids for epithelial origin, stem cell features, frameshift mutation frequency, MSI-H, chromosome instability, and heterogeneity.
- Utilized intra-cecal implantation of organoid-derived tumor fragments for the orthotopic model.
Main Results:
- Organoids exhibited MSI-H, stem cell features, and significant intra- and inter-tumor heterogeneity.
- The orthotopic model demonstrated progressive tumor growth, adenocarcinoma development with mucinous features, and distant metastasis to the liver and lymph nodes.
- The orthotopic model expressed frameshift peptides, indicating potential for neoantigen-based therapies.
Conclusions:
- Established organoids serve as a valuable tool for studying MMRd cancer biology.
- The orthotopic model, with its metastatic potential and MSI-H characteristics, is suitable for evaluating novel therapeutic strategies, including neoantigen vaccines and combination therapies.
