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Simple Summary Biliary tract cancer (BTC) is often refractory to conventional therapeutics and is difficult to diagnose in the early stages. In addition, the pathogenesis of BTC is not fully understood, despite recent advances in cancer genome analysis. To address these issues, the development of fine disease models is critical for BTC. Although still limited in number, there are various platforms for genetic models of BTC owing to newly emerging technology. Among these, implantation-based models have recently drawn attention for their convenience, flexibility, and scalability. To highlight the relevance of this approach, we comprehensively summarize the advantages and disadvantages of BTC models developed using diverse approaches. Currently available research data on intra- and extrahepatic cholangiocarcinoma and gallbladder carcinoma are presented in this review. This information will likely help in selecting the optimal models for various applications and develop novel innovative models based on these technologies. 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.

Ovarian cancer (OC) is one of the leading causes of female cancer death. Recent studies have documented its extensive variations as a disease entity, in terms of cell or tissue of origin, pre-cancerous lesions, common mutations, and therapeutic responses, leading to the notion that OC is a generic term referring to a whole range of different cancer subtypes. Despite such heterogeneity, OC treatment is stereotypic; aggressive surgery followed by conventional chemotherapy could result in chemo-resistant diseases. Whereas molecular-targeted therapies will become shortly available for a subset of OC, there still remain many patients without effective drugs, requiring development of groundbreaking therapeutic agents. In preclinical studies for drug discovery, cancer cell lines used to be the gold standard, but now this has declined due to frequent failure in predicting therapeutic responses in patients. In this regard, patient-derived cells and tumors are gaining more attention in precise and physiological modeling of in situ tumors, which could also pave the way to implementation of precision medicine. In this article, we comprehensively overviewed the current status of various platforms for patient-derived OC models. We highly appreciate the potentials of organoid culture in achieving high success rate and retaining tumor heterogeneity.

The metaplastic epithelium of the transformation zone (TZ) including the squamocolumnar junction (SCJ) of the uterine cervix is a prime target of human papilloma virus (HPV) infection and subsequent cancer development. Due to the lack of adequate in vitro models for SCJ, however, investigations into its physiological roles and vulnerability to carcinogenesis have been limited. By using Matrigel-based three-dimensional culture techniques, we propagated organoids derived from the normal SCJ region, along with metaplastic squamous cells in the TZ. Consisting predominantly of squamous cells, organoids basically exhibited a dense structure. However, at least in some organoids, a small but discrete population of mucin-producing endocervix cells co-existed adjacent to the squamous cell population, virtually recapitulating the configuration of SCJ in a TZ background. In addition, transcriptome analysis confirmed a higher expression level of many SCJ marker genes in organoids, compared to that in the immortalized cervical cell lines of non-SCJ origin. Thus, the obtained organoids appear to mimic cervical SCJ cells and, in particular, metaplastic squamous cells from the TZ, likely providing a novel platform in which HPV-driven cervical cancer development could be investigated.

Remarkable upregulation of the NRF2 (NFE2L2)-related transcription factor NRF3 (NFE2L3) in several cancer tissues and its correlation with poor prognosis strongly suggest the physiological function of NRF3 in tumors. Indeed, we had recently uncovered the function of NRF3, which promotes cancer cell proliferation by p53 degradation via the 20S proteasome. Nevertheless, the molecular mechanism underlying the induction of NRF3 gene expression in cancer cells is highly elusive. We herein describe that NRF3 upregulation is induced by the &beta, catenin/TCF4 complex in colon cancer cells. We first confirmed high NRF3 mRNA expression in human colon cancer specimens. The genome database indicated that the human NRF3 gene possesses a species-conserved WRE sequence (TCF/LEF consensus element), implying that the &beta, catenin/TCF complex activates NRF3 expression in colon cancer. Consistently, we observed that the &beta, catenin/TCF4 complex mediates NRF3 expression by binding directly to the WRE site. Furthermore, inducing NRF3 activates cell proliferation and the expression of the glucose transporter GLUT1. The existence of the &beta, catenin/TCF4-NRF3 axis was also validated in the intestine and organoids of Apc-deficient mice. Finally, the positive correlation between NRF3 and &beta, catenin target gene expression strongly supports our conclusion. Our findings clearly demonstrate that NRF3 induction in cancer cells is controlled by the Wnt/&beta, catenin pathway.