Xenografting human cancer cells in mice is a well-established method for studying the development of cancers and for testing the efficacy of chemotherapeutic drugs. For xenografts to be successful, the host mice must be immunodeficient, which can be achieved by using mice deficient in Rag1 to deplete mature B- and T-lymphocytes. However, only a small number of Rag1−/− strains capable of accepting xenografts have been developed, and thus, the genetic diversity of these mouse strains is limited. Importantly, the National Institutes of Health recently highlighted a lack of genetic diversity in pre-clinical studies as one of the main reasons for failure of clinical trials.

In their study, Muneer Hasham and colleagues pave the way to overcoming this issue by generating five genetically diverse, xenograft-competent Rag1-deficient mouse strains, which cover 90% of the known allelic diversity in the mouse genome. They characterised these strains by subcutaneously xenografting breast cancer, leukaemia and glioma cell lines and assessing tumour progression by size, cellular composition and stromal invasion. Here, the authors found that tumour size varies more significantly between strains than between cancer types, and this correlates with variable levels of collagen in the tumour microenvironment. Additionally, stromal cell infiltrations into the tumour varies between mouse strains, and this impacts the density of neoplastic cells within tumours. Finally, the authors identified increases in a number of pro-inflammatory cytokines in the blood of these mice, which are associated with enhanced tumour growth. Here, the authors found that cytokines keratinocyte-derived chemokine (KC) and IL-6 are highly upregulated in most xenografted strains, while a further subset of pro-inflammatory cytokines and chemokines only increase in strains with the largest tumours, suggesting strain-specific responses.

Overall, this study highlights the impact of murine genetic diversity on tumour microenvironment and progression upon xenografting multiple cancer cell types. The generation of five new genetically diverse Rag1−/− mouse strains that are xenograft competent expands the preclinical toolkit to better recapitulate human genetic diversity. Ultimately, this can produce more translatable findings for clinical trials testing novel treatments for various cancers.

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