Transposon Insertion Mutagenesis in Mice for Modeling Human Cancers: Critical Insights Gained and New Opportunities

Abstract

Transposon mutagenesis has been used to model many types of human cancer in mice, leading to the discovery of novel cancer genes and insights into the mechanism of tumorigenesis. For this review, we identified over twenty types of human cancer that have been modeled in the mouse using Sleeping Beauty and piggyBac transposon insertion mutagenesis. We examine several specific biological insights that have been gained and describe opportunities for continued research. Specifically, we review studies with a focus on understanding metastasis, therapy resistance, and tumor cell of origin. Additionally, we propose further uses of transposon-based models to identify rarely mutated driver genes across many cancers, understand additional mechanisms of drug resistance and metastasis, and define personalized therapies for cancer patients with obesity as a comorbidity.

Contemporary Transposon Tools: A Review and Guide through Mechanisms and Applications of Sleeping Beauty, piggyBac and Tol2 for Genome Engineering

“…Therefore, choosing the right system for the right application is essential. For example, the preferential integration of Tol2 and PB into TSSs is advantageous for promoter/enhancer trapping [ 108 , 159 ], while the close-to-random insertion profile of SB enables to perform highly unbiased screens and detection of features that would be unlikely reached with other methods [ 160 ]. As discussed in previous sections, PB was shown to be highly active in a variety of species from yeast to humans, a property that makes it an almost universal tool for mutagenesis screens [ 161 , 162 ].…”

“…Tol2 enabled mutagenic screens in this model [ 159 , 163 ], and remains a major tool in zebrafish research [ 165 ]. Transposon-based screens are also currently of particular interest in cancer research to identify oncogenes, drivers of metastasis and predictors of therapy resistance [ 160 ]. As high-throughput technologies are increasingly accessible and discoveries require more data and efforts, we predict that transposon-based mutagenic screens will play a major role in unraveling the remaining mysteries present within genomic DNA.…”

Silencing of Histone Deacetylase 6 Decreases Cellular Malignancy and Contributes to Primary Cilium Restoration, Epithelial-to-Mesenchymal Transition Reversion, and Autophagy Inhibition in Glioblastoma Cell Lines

“…Noorani et al [67] demonstrated, by means of PiggyBac mutagenesis [68] and exome sequencing, the targets of EGFR amplification or EGFRvIII in gliomas. HDAC6 was not among those targets.…”

“…It is therefore unclear how our results might translate into an in vivo setting. Although we do not include in vivo experiments, testing HDAC6 knock-down in mouse experiments in future studies is important, e.g., using mouse models of glioblastoma as those recently reviewed by Noorani [73], who discusses on more faithful mouse models resembling human gliomas, including new cre/LoxP transgenic lines that allow more accurate cell targeting of genetic recombination, Sleeping Beauty [74], and PiggyBac transposons [68] for the integration of transgenes and genetic screens and CRISPR-cas9 [75] for generating genetic knockout and functional screens. Applications of these technologies are providing novel insights into the functional genetic drivers of gliomagenesis, how these genes cooperate with one another, and the potential cells-of-origin of gliomas, knowledge of which is critical to the development of targeted treatments for patients in the clinic [73].…”

Understanding How Genetic Mutations Collaborate with Genomic Instability in Cancer

“…In later screens, Cre-inducible SB or PB transposase was used to restrict transposon mutagenesis to specific tissues such as B-cells, liver, and the gastrointestinal tract [82][83][84]. In addition, transposon screens were employed to find drivers of many other tumor types including breast, lung, prostate, thyroid, melanoma, and medulloblastoma (reviewed in [85][86][87]). Together, these studies showed that transposon mutagenesis can drive tumorigenesis in wild type or genetically-predisposed backgrounds.…”