Annual Report 2019

Division of Rare Cancer Research

Tadashi Kondo, Rei Noguchi, Yuki Yoshimatsu, Yooksil Sin, Akane Sei

Introduction

 The research goal of the Division of Rare Cancer Research is to create the innovative seeds for better clinical outcomes for rare cancer patients. A rare cancer is defined as a cancer with incidence of less than six per 100,000 annually. Rare cancer includes approximately 200 cancer types, and despite the rarity of each rare cancer, they represent approximately 15% in total of all cancer cases in Japan. Thus, rare cancer research deals with wide-ranging subjects for a large number of cancer patients. We consider that the fundamental problem of rare cancer research is a lack of research resources such as cancer models, biobank materials and databases. Thus, we address these issues. The establishment of patient-derived cancer models, and the database for meta-analysis of genes are efforts to solve problems related to the limited amount of clinical material. Re-purposing of cancer drugs is a practical approach to rare cancers, and the experimental systems for re-purposing of cancer drugs were created in our laboratory. These include the high-throughput screening system and the application of a Connectivity Map and other bioinformatics modalities. Studies for individual rare cancers have also been conducted in our laboratory. Using global gene and protein data, we identified candidates for novel innovative seeds, e.g. predictive and prognostic biomarkers. To facilitate the research and development of novel medical seeds, we have developed proteogenomics software. Our experience and fundamental systems for rare cancer research will be applicable for major cancer research.

Research activities

1. Establishment of fundamental research system

• Patient-derived cancer models were created from the clinical materials of sarcoma patients.
• Screening system for the study of re-localization of cancer drugs was established and used for the cell panel.
• Platform of bioinformatics such as the original Connectivity Map was created and applied to the study of re-localization of cancer drugs.
• Database of gene status of rare cancer was created using a bioinformatics approach.

2. Study of individual rare cancers

 The identification of therapeutic targets and biomarkers was undertaken using clinical materials and our original cell panel. The biomarker candidates to predict the resistance of molecular anti-cancer drugs and those to evaluate the invasion potentials of tumors were identified by a multi-omics approach. Their molecular backgrounds and validation using additional cases are under consideration.

3. Reverse innovation

 The research platforms were developed with the idea that they will be applicable to other malignancies.

Education

 Three PhD students and two post-doctoral fellows were trained.

Future prospects

 Our research activities will benefit patients with rare cancers. The fundamental system for rare cancer research will be applicable to the research of all cancers.

List of papers published in 2019

Journal

1. Oyama R, Kito F, Takahashi M, Sakumoto M, Shiozawa K, Qiao Z, Noguchi R, Kubo T, Toki S, Nakatani F, Yoshida A, Kawai A, Kondo T. Establishment and characterization of a novel dedifferentiated chondrosarcoma cell line, NCC-dCS1-C1. Hum Cell, 32:202-213, 2019

2. Shiozawa K, Oyama R, Takahashi M, Kito F, Hattori E, Yoshida A, Kawai A, Ono M, Kondo T. Species-Specific Quantitative Proteomics Profiles of Sarcoma Patient-Derived Models Closely Reflect Their Primary Tumors. Proteomics Clin Appl, 13:e1900054, 2019

3. Asano N, Matsuzaki J, Ichikawa M, Kawauchi J, Takizawa S, Aoki Y, Sakamoto H, Yoshida A, Kobayashi E, Tanzawa Y, Nakayama R, Morioka H, Matsumoto M, Nakamura M, Kondo T, Kato K, Tsuchiya N, Kawai A, Ochiya T. A serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes. Nat Commun, 10:1299, 2019

4. Oyama R, Kito F, Qiao Z, Sakumoto M, Shiozawa K, Toki S, Yoshida A, Kawai A, Kondo T. Establishment of novel patient-derived models of dermatofibrosarcoma protuberans: two cell lines, NCC-DFSP1-C1 and NCC-DFSP2-C1. In Vitro Cell Dev Biol Anim, 55:62-73, 2019

5. Hattori E, Oyama R, Kondo T. Systematic Review of the Current Status of Human Sarcoma Cell Lines. Cells, 8:pii: E157, 2019

6. Patel N, Wang J, Shiozawa K, Jones KB, Zhang Y, Prokop JW, Davenport GG, Nihira NT, Hao Z, Wong D, Brandsmeier L, Meadows SK, Sampaio AV, Werff RV, Endo M, Capecchi MR, McNagny KM, Mak TW, Nielsen TO, Underhill TM, Myers RM, Kondo T, Su L. HDAC2 Regulates Site-Specific Acetylation of MDM2 and Its Ubiquitination Signaling in Tumor Suppression. iScience, 13:43-54, 2019

7. Qiao Zhiwei, Kondo Tadashi. Identification of cantharidin as a drug candidate for glioblastoma by using a Connectivity Map-based approach. Journal of Electrophoresis, 63:9-14, 2019

8. Qiao Zhiwei, Kondo Tadashi. Screening of a growth inhibitor library of sarcoma cell lines to identify potent anti-cancer drugs. Journal of Electrophoresis, 63:1-7, 2019

9. Oyama Rieko, Takahashi Mami, Kito Fusako, Sakumoto Marimu, Takai Yoko, Shiozawa Kumiko, Qiao Zhiwei, Toki Shunichi, Tanzawa Yoshikazu, Yoshida Akihiko, Kawai Akira, Kondo Tadashi. ESTABLISHMENT AND CHARACTERIZATION OF PATIENT-DERIVED PLEOMORPHIC RHABDOMYOSARCOMA MODELS. 組織培養研究, 38:1-12, 2019

10. Kito F, Oyama R, Sakumoto M, Shiozawa K, Qiao Z, Toki S, Yoshida A, Kawai A, Kondo T. Establishment and characterization of a novel cell line, NCC-MFS1-C1, derived from a patient with myxofibrosarcoma. Hum Cell, 32:214-222, 2019

11. Tajima T, Kito F, Yoshida A, Kawai A, Kondo T. Calreticulin as A Novel Potential Metastasis-Associated Protein in Myxoid Liposarcoma, as Revealed by Two-Dimensional Difference Gel Electrophoresis. Proteomes, 7:pii: E13, 2019

12. Jia X, Chen C, Chen L, Yu C, Kondo T. Decorin as a prognostic biomarker in patients with malignant peripheral nerve sheath tumors. Oncol Lett, 17:3517-3522, 2019

13. Okimoto RA, Wu W, Nanjo S, Olivas V, Lin YK, Ponce RK, Oyama R, Kondo T, Bivona TG. CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs. J Clin Invest, 129:3401-3406, 2019

14. Hirata M, Asano N, Katayama K, Yoshida A, Tsuda Y, Sekimizu M, Mitani S, Kobayashi E, Komiyama M, Fujimoto H, Goto T, Iwamoto Y, Naka N, Iwata S, Nishida Y, Hiruma T, Hiraga H, Kawano H, Motoi T, Oda Y, Matsubara D, Fujita M, Shibata T, Nakagawa H, Nakayama R, Kondo T, Imoto S, Miyano S, Kawai A, Yamaguchi R, Ichikawa H, Matsuda K. Integrated exome and RNA sequencing of dedifferentiated liposarcoma. Nat Commun, 10:5683, 2019

15. Asano N, Takeshima H, Yamashita S, Takamatsu H, Hattori N, Kubo T, Yoshida A, Kobayashi E, Nakayama R, Matsumoto M, Nakamura M, Ichikawa H, Kawai A, Kondo T, Ushijima T. Epigenetic reprogramming underlies efficacy of DNA demethylation therapy in osteosarcomas. Sci Rep, 9:20360, 2019

Book

1. Kawase T, Chen Y, Ohki R. IER5 Is a p53-Regulated Activator of HSF1 That Contributes to Promotion of Cancer. In: Asea A, Kaur P (ed), Heat Shock Proteins in Signaling Pathways. Heat Shock Proteins, vol 17, Switzerland, Springer, pp 253-272, 2019