Annual Report 2020
Department of Cancer Model Development
Toshio Imai, Yukari Totsuka, Masami Sakano, Yukiko Nakamura, Yutaka Shoji, Yumi Miyamoto, Yukie Matsumura
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.
The Team and What We Do
We willingly 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
The basic research activities of the Department of Cancer Model Development are focused on studies of recapitulation of multi-step carcinogenesis for diverse organs through an in vitro approach. Whereas both genetic and environmental factors cooperate for tumorigenesis in vivo, we demonstrated that combined introduction of cancer-related genetic alterations in cultured murine primary epithelial cells, so-called organoids, could lead to the development of adenocarcinomas in the dorsal skin of immunodeficient mice. Notably, tumor initiation and subsequent stepwise progression from normal cells via precancerous lesions to carcinoma could be accurately recapitulated for various vital organs in a cell-autonomous manner. By taking this approach, genetic and/or environmental interactions toward tumorigenesis could be conveniently investigated in vitro, which would likely accelerate the elucidation of the molecular mechanisms underlying carcinogenesis. Although heterogeneous Trp53-knockout organoids did not form carcinomas, the in vitro treatment of genotoxic carcinogens, e.g., acrylamide (AA) and 7,12-dimethylbenz(a)anthracene (DMBA), could induce carcinoma/carcinoma-like tissues. Although these results partly resembled those induced in AA- or DMBA-treated mouse models, we found that they were partly different from those in animal models, e.g., genotypes in the induced tumors. Therefore, the comparative analysis of an organoid-based carcinogenesis model to an animal model will be considered to elucidate molecular mechanisms of early stages of carcinogenesis.
Future Prospects
Staff of the Department of Cancer Model Development are united in their resolve to establish wide-ranging cancer animal model panels, which could be selected depending on their intended use.
List of papers published in 2020
Journal
1. Totsuka Y, Watanabe M, Lin Y. New horizons of DNA adductome for exploring environmental causes of cancer. Cancer Sci, 112:7-15, 2021
2. Kobayashi T, Toyoda T, Tajima Y, Kishimoto S, Tsunematsu Y, Sato M, Matsushita K, Yamada T, Shimamura Y, Masuda S, Ochiai M, Ogawa K, Watanabe K, Takamura-Enya T, Totsuka Y, Wakabayashi K, Miyoshi N. o-Anisidine Dimer, 2-Methoxy-N(4)-(2-methoxyphenyl) Benzene-1,4-diamine, in Rat Urine Associated with Urinary bladder Carcinogenesis. Chem Res Toxicol, 34:912-919, 2021
3. Lu KT, Yamamoto T, McDonald D, Li W, Tan M, Moi ML, Park EC, Yoshimatsu K, Ricciardone M, Hildesheim A, Totsuka Y, Nanbo A, Putcharoen O, Suwanpimolkul G, Jantarabenjakul W, Paitoonpong L, Handley FG, Bernabe KG, Noda M, Sonoda M, Brennan P, Griffin DE, Kurane I. U.S.-Japan cooperative medical sciences program: 22nd International Conference on Emerging Infectious Diseases in the Pacific Rim. Virology, 555:71-77, 2021
4. Totsuka Y, Maesako Y, Ono H, Nagai M, Kato M, Gi M, Wanibuchi H, Fukushima S, Shiizaki K, Nakagama H. Comprehensive analysis of DNA adducts (DNA adductome analysis) in the liver of rats treated with 1,4-dioxane. Proc Jpn Acad Ser B Phys Biol Sci, 96:180-187, 2020
5. Tajima Y, Toyoda T, Hirayama Y, Matsushita K, Yamada T, Ogawa K, Watanabe K, Takamura-Enya T, Totsuka Y, Wakabayashi K, Miyoshi N. Novel o-Toluidine Metabolite in Rat Urine Associated with Urinary Bladder Carcinogenesis. Chem Res Toxicol, 33:1907-1914, 2020
6. Kawanishi M, Yoneda R, Totsuka Y, Yagi T. Genotoxicity of micro- and nano-particles of kaolin in human primary dermal keratinocytes and fibroblasts. Genes Environ, 42:16, 2020
7. Mimaki S, Watanabe M, Kinoshita M, Yamashita R, Haeno H, Takemura S, Tanaka S, Marubashi S, Totsuka Y, Shibata T, Nakagama H, Ochiai A, Nakamori S, Kubo S, Tsuchihara K. Multifocal origin of occupational cholangiocarcinoma revealed by comparison of multilesion mutational profiles. Carcinogenesis, 41:368-376, 2020
8. Naruse M, Masui R, Ochiai M, Maru Y, Hippo Y, Imai T. An organoid-based carcinogenesis model induced by in vitro chemical treatment. Carcinogenesis, 41:1444-1453, 2020
9. Matsuura T, Maru Y, Izumiya M, Hoshi D, Kato S, Ochiai M, Hori M, Yamamoto S, Tatsuno K, Imai T, Aburatani H, Nakajima A, Hippo Y. Organoid-based ex vivo reconstitution of Kras-driven pancreatic ductal carcinogenesis. Carcinogenesis, 41:490-501, 2020