Annual Report 2022

Department of Cancer Model Development

Toshio Imai, Hiroe Nozaki

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 of colorectal cancer. On the other hand, gene mutation patterns in patient-derived xenografts (PDXs) from several types of tumors, such as breast cancer, sarcoma and acute myeloid leukemia, were reported to be altered in PDXs compared with the original tumors. Therefore, further analysis is required 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, co-culture systems with cancer organoids and stromal cells, and PDX models for translational research and to screening and evaluating prospective candidates for new molecular-targeted drugs.

Research Activities

 The possible effects of E7386, a selective inhibitor of b-catenin/CBP signaling, were evaluated using PDX models, organoids and corresponding cancer-associated fibroblasts (CAFs) derived from patients with colorectal cancer. In conclusion, the present comprehensive molecular analysis of E7386-treated colorectal cancer organoids, CAFs and PDXs revealed that several independent molecular mechanisms may be involved upstream of the reduction of cell viability.

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 2022

Journal

1. Ishigamori R, Naruse M, Hirata A, Maru Y, Hippo Y, Imai T. The potential of organoids in toxicologic pathology: Histopathological and immunohistochemical evaluation of a mouse normal tissue-derived organoid-based carcinogenesis model. Journal of toxicologic pathology, 35:211-223, 2022

2. Imai T, Naruse M, Ochiai M, Matsumoto K, Ikeda S, Kani M, Kato Y, Hirayama A, Soga T, Hori Y, Yokoi A, Ochiai A. Different types of reactions to E7386 among colorectal cancer patient-derived organoids and corresponding CAFs. Oncology letters, 24:221, 2022

3. Imai T, Hippo Y. Editorial: Development of in vitro toxicology methods using organoid systems and toxicogenomic approaches. Frontiers in genetics, 13:1030580, 2022