Recent Advances in Implantation-Based Genetic Modeling of Biliary Carcinogenesis in Mice

Abstract

Epithelial cells in the biliary system can develop refractory types of cancers, which are often associated with inflammation caused by viruses, parasites, stones, and chemicals. Genomic studies have revealed recurrent genetic changes and deregulated signaling pathways in biliary tract cancer (BTC). The causal roles have been at least partly clarified using various genetically engineered mice. Technical advances in Cre-LoxP technology, together with hydrodynamic tail injection, CRISPR/Cas9 technology, in vivo electroporation, and organoid culture have enabled more precise modeling of BTC. Organoid-based genetic modeling, combined with implantation in mice, has recently drawn attention as a means to accelerate the development of BTC models. Although each model may not perfectly mimic the disease, they can complement one another, or two different approaches can be integrated to establish a novel model. In addition, a comparison of the outcomes among these models with the same genotype provides mechanistic insights into the interplay between genetic alterations and the microenvironment in the pathogenesis of BTCs. Here, we review the current status of genetic models of BTCs in mice to provide information that facilitates the wise selection of models and to inform the future development of ideal disease models.

Two-Way Development of the Genetic Model for Endometrial Tumorigenesis in Mice: Current and Future Perspectives

“…Another new way is to develop ex vivo/in vivo hybrid models based on genetic engineering of primary endometrial cells or organoids. Given the rapid application of organoids and CRISPR/Cas9 technology in many research fields ( Izumiya et al, 2021 ), it is probable that an increasing number of organoid-based models for EC will be developed. However, only a few such models have been documented for FRT organs to date ( Zhang et al, 2019 ; Lohmussaar et al, 2020 ; Maru et al, 2021a ; Maru et al, 2021b ), including ours being the first and only EC model ( Maru et al, 2021a ).…”

Twists and turns in Kras-driven tumor initiation

“…By integrating lentiviral gene transduction of murine organoids and their subsequent allograft implantation in immunodeficient mice, we assessed the tumorigenicity of each oragnoid [ 2 – 4 ]. In most cases, the outcomes were essentially similar to those observed in GEM models, even in the absence of an organ-specific microenvironment or cellular immunity, highlighting the validity and robustness of this ex vivo model [ 5 , 6 ]. Although at least two genetic alterations are usually required for developing neoplasms, mutant Kras alone in the pancreatic organoid exceptionally gave rise to PanIN-like lesions in 50% of tested cases [ 3 ], confirming the critical roles of mutant Kras in pancreatic tumorigenesis using this model.…”

AMPAR receptor inhibitors suppress proliferation of human small cell lung cancer cell lines

“…In experiments using human cells, immunoproficient mice cannot be used as hosts. Therefore, if the host immune reaction is required for the antitumor effect of a drug, this effect cannot be correctly determined or detected in immunodeficient mice 36 . Thus, it is possible that AMPAR inhibitors may require host anticancer immunity to fully exert their anti−growth effect on SCLC tumors in vivo.…”