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Published on: November 6, 2019
Genetically diverse mouse platform to xenograft cancer cells
Jennifer K Sargent1, Mark A Warner1, Benjamin E Low1
1The Jackson Laboratory for Mouse Genetics, 600 Main Street, Bar Harbor, ME 04609, USA.
Abstract:
The lack of genetically diverse preclinical animal models in basic biology and efficacy testing has been cited as a potential cause of failure in clinical trials. We developed and characterized five diverse RAG1 null mouse strains as models that allow xenografts to grow. In these strains, we characterized the growth of breast cancer, leukemia and glioma cell lines. We found a wide range of growth characteristics that were far more dependent on strain than tumor type. For the breast cancer cell line, we characterized the spectrum of xenograft/tumor growth at structural, histological, cellular and molecular levels across each strain, and found that each strain captures unique structural components of the stroma. Furthermore, we showed that the increase in tumor-infiltrating myeloid CD45+ cells and the amount of circulating cytokine IL-6 and chemokine KC (also known as CXCL1) is associated with a higher tumor size in different strains. This resource is available to study established human xenografts, as well as difficult-to-xenograft tumors and growth of hematopoietic stems cells, and to decipher the role of myeloid cells in the development of spontaneous cancers.
Insights
New mouse models with diverse genetics enable better preclinical testing for cancer xenografts. These models show varied tumor growth, aiding research into cancer development and treatment strategies.
Area of Science:
- Preclinical animal models
- Cancer research
- Immunology
Background:
- Limited genetic diversity in preclinical models may contribute to clinical trial failures.
- Development of genetically diverse mouse strains is crucial for accurate disease modeling.
Purpose of the Study:
- To develop and characterize diverse RAG1 null mouse strains for xenograft studies.
- To assess the utility of these strains in modeling breast cancer, leukemia, and glioma growth.
Main Methods:
- Generation and characterization of five RAG1 null mouse strains.
- Xenotransplantation of human cancer cell lines (breast cancer, leukemia, glioma).
- Analysis of tumor growth at structural, histological, cellular, and molecular levels.
Main Results:
- Tumor growth varied significantly across strains, more so than by tumor type.
- Each strain exhibited unique stromal components in breast cancer xenografts.
- Increased myeloid CD45+ cells and elevated IL-6/KC (CXCL1) levels correlated with larger tumor size.
Conclusions:
- These diverse RAG1 null mouse strains provide a valuable resource for studying xenografts, difficult-to-model tumors, and hematopoietic stem cell growth.
- The models facilitate research into the role of myeloid cells in cancer development and response to therapy.
