Dual Recombinase–Based Mouse Models Help Decipher Cancer Biology and Targets for Therapy

Abstract

The advent of next-generation sequencing (NGS) and single-cell profiling technologies has revealed the complex and heterogenous ecosystem of human tumors under steady-state and therapeutic perturbation. Breakthroughs in the development of genetically engineered mouse models (GEMM) of human cancers that are based on the combination of two site-specific recombinase systems [dual-recombinase system (DRS)] offer fundamental new possibilities to elucidate and understand critical drivers of the diverse tumor phenotypes and validate potential targets for therapy. Here, we discuss opportunities DRS-based cancer GEMMs offer to model, trace, manipulate, and functionally investigate established cancers, their interactions with the host, and their response to therapy.

In vivosequential mutagenesis in germinal center B cells using a dual-recombinase approach: FOXO1 re-expression upon FOXO1 knockout rescues class switch recombination

“…Site-specific recombination systems, such as Cre/loxP, are key technologies to study gene function and (patho)physiological processes in vivo . Dual-recombinase approaches represent a further technical development that enables more precise disease modelling, in particular with respect to multistep genetic manipulations and lineage tracing 1,2 . However, one limitation of the currently available systems is that recombinases are expressed from different loci, hereby requiring the generation of complex compound mutant mice – containing separate transgenes encoding the recombinases together with the respective target alleles – and thus complicating the analysis both in terms of breeding time frame and fidelity of sequential mutagenesis at the level of individual cells.…”