Annual Report 2021
Department of Cancer Model Development
Toshio Imai, Hiroe Nozaki, Masami Sakano, Yukiko Nakamura, Yumi Miyamoto
Introduction
In preclinical studies for anticancer drugs, in vitro and in vivo models derived from clinical tumor specimens are considered to provide more accurate prediction data for the clinical efficacy of candidate agents than models using conventionally established cancer cell lines. A pivotal role of this department is the establishment of cancer organoids, cell aggregates consisting of variously differentiated cells including cancer stem cells, and tumor-harboring animal models (cancer tissue/cell-transplanted immune-deficient mice). These in vitro and in vivo models are used for efficacy evaluations and pharmacodynamic biomarker discovery of molecular-targeted drugs. One of the goals is to set up flexible models that have greater accuracy than previous ones using established cancer cell lines.
We reported that histopathological morphology, gene mutation and gene expression patterns, which characterize each cancer case, were found to be almost as maintained in patient-derived 3D-cultured organoids/xenografts (PDXs) as those in original surgical specimens of colorectal cancer. On the other hand, gene mutation patterns in PDXs from several types of tumors, such as breast cancer, sarcoma and acute myeloid leukemia were reported to be altered in PDXs compared to the original tumors. Therefore, further analysis is needed to clarify the characteristics of patient-derived cancer models in major types of tumors.
The Team and What We Do
We contribute to establishing useful in vitro and in vivo models, including cancer organoids and PDX models for translational research and to screening and evaluating prospective candidates for new molecular-targeted drugs.
Research activities
Genomic and phenotypic alterations in PDXs of endometrial carcinomas were evaluated compared to the original tumors. As a result, PDXs of endometrioid carcinomas were found to maintain their histomorphological characteristics; however, those of carcinosarcomas came to be more dominated by sarcomatous components compared to the original tumors. In addition, additional genomic changes in PDXs were noted compared to those in original tumors in several cases. These results suggest that genomic and phenotypic checking against primary tumors are needed for the application of endometrial carcinoma PDXs to drug screening.
Future Prospects
The staff of the Department of Cancer Model Development are united in their resolve to establish wide-ranging cancer animal model panels that can be selected depending on their intended use.
List of papers published in 2021
Journal
1. Komiya M, Ishigamori R, Naruse M, Ochiai M, Miyoshi N, Imai T, Totsuka Y. Establishment of Novel Genotoxicity Assay System Using Murine Normal Epithelial Tissue-Derived Organoids. Frontiers in genetics, 12:768781, 2021
2. Naruse M, Ishigamori R, Imai T. The Unique Genetic and Histological Characteristics of DMBA-Induced Mammary Tumors in an Organoid-Based Carcinogenesis Model. Frontiers in genetics, 12:765131, 2021
3. Machida Y, Imai T. Different properties of mammary carcinogenesis induced by two chemical carcinogens, DMBA and PhIP, in heterozygous BALB/c Trp53 knockout mice. Oncology letters, 22:738, 2021