Building a healthy mouse model ecosystem to interrogate cancer biology

In a recent study, Sargent et al. characterise several novel Rag1-/- mouse strains and demonstrate that genetic background strongly influences xenograft development and phenotype. Here, we discuss this work within the broader context of cancer mouse modelling. We argue that new technologies will enable insights into how specific models align with human disease states and that this knowledge can be used to develop a diverse ecosystem of complementary mouse models of cancer. By utilising these diverse, well-characterised models to provide multiple perspectives on specific cancers, it should be possible to reduce the inappropriate attrition of sound hypotheses while protecting against false positives. Furthermore, careful re-introduction of biological variation, be that through outbred populations, environmental diversity or including animals of both sexes, can ensure that results are more broadly applicable and are less impacted by particular traits of homogeneous experimental populations. Thus, careful characterisation and judicious use of an array of mouse models provides an opportunity to address some of the issues surrounding both the reproducibility and translatability crises often referenced in pre-clinical cancer research.