Annual Report 2024

Division of Collaborative Research and Development

Akihiro Ohashi, Toru Kiyono, Tomoko Yamamori, Ryo Kamata, Chiaki Mashima, Hitoshi Saito, Emi Ito, Misato Kamini, Gaku Yamamoto, Hiroki Yamashita, Takuya Nakatsuru, Keita Hirouchi, Kumi Kinoshita, Yukie Kashima

Introduction

 We are conducting drug discovery projects aimed at developing novel cancer therapeutics by integrating basic and clinical research in a "translational research" framework. Our research focus is "genomic instability in cancer", which results from defects in DNA replication/repair or from chromosomal missegregation, especially on how genomic instability impose survival stresses in cancer cells, how cancer cells evade these survival stresses, and how genomic stress-mediated survival stress causes cancer vulnerabilities as "fitness-cost". To investigate biological significance of "genomic instability in cancer" more comprehensively, we are utilizing multiple research assets including chemical biology, molecular and cellular biology, omics analyses (such as transcriptomics and metabolomics), and animal models. We have also established research assets of single-cell RNA sequencing and spatial analysis for clinical specimens to clarify "genomic instability" in tumor microenvironment. Additionally, we are promoting collaborative research with global institutions and biotech companies, such as the Frederick National Laboratory for Cancer Research (FNLCR) and Arjuna Therapeutics.

The Team and What We Do

 In collaboration with Hokkaido University and the Division of Cancer Immunology at NCC EPOC, we have revealed that WEE1 confers resistance to KRAS^G12C inhibitors in non-small cell lung cancer (published in Cancer Letters 2025). In this paper, we demonstrated that the WEE1 inhibitor is a synergistic partner for the KRAS inhibitor in KRASG12C-mutant lung cancer, and dual inhibition of WEE1 and KRASG12C also restores sensitivity in resistant cancer cells. In addition, we have also collaborated with Jikei University School of Medicine on PARP inhibitor project (published in Sci. Rep. 2025), in which we demonstrated that PARP inhibitors can induce cellular senescence in homologous recombination-proficient (HRP) ovarian cancer cells, as well as in other cancer cell types. These findings suggest that, in addition to their well-known role in synthetic lethality, PARP inhibitors may also have the potential to activate immune responses in the tumor. Furthermore, we have established research platforms for studying the tumor microenvironment, including protocols for single-cell and spatial analyses using clinical specimens. We have also presented the results of our collaborative research with FNLCR and Arjuna Therapeutics at international and domestic conferences.

Education

 We provided guidance on basic and translational research using chemical biology and molecular biology techniques for two Ph.D. candidates and one MS candidate at the affiliated graduate school (University of Tokyo) on their degree topics. We also hosted two external graduate students as visiting researchers, providing them with guidance on basic and translational research. These two external graduate students published their Ph.D. project in international scientific journals.

Future Prospects

 We will utilize cutting-edge omics technologies with clinical specimens to elucidate the molecular mechanisms of therapeutic resistance in the cancer microenvironment. Based on these latest findings, we will advance research and development aimed at creating new therapeutic agents, in collaboration with academic institutions, biotech companies, and pharmaceutical companies both domestically and internationally.

List of papers published in 2024

Journal

1. Ogawa A, Izumikawa K, Tate S, Isoyama S, Mori M, Fujiwara K, Watanabe S, Ohga T, Jo U, Taniyama D, Kitajima S, Tanaka S, Onji H, Kageyama SI, Yamamoto G, Saito H, Morita TY, Okada M, Natsumeda M, Nagahama M, Kobayashi J, Ohashi A, Sasanuma H, Higashiyama S, Dan S, Pommier Y, Murai J. SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis. Molecular cell, 85:894-912.e10, 2025

2. Minamide T, Minakata N, Yamashita R, Sakashita S, Yoda Y, Ohashi A, Aoshima M, Kobayashi S, Yano T. Oxygen saturation imaging elucidates tumor heterogeneity in gastric cancer. DEN open, 5:e70077, 2025

3. Sohel HI, Kiyono T, Zahan UF, Razia S, Ishikawa M, Yamashita H, Kanno K, Sonia SB, Nakayama K, Kyo S. Establishment of a Novel In Vitro and In Vivo Model to Understand Molecular Carcinogenesis of Endometriosis-Related Ovarian Neoplasms. International journal of molecular sciences, 26:1995, 2025

4. Uchibori Y, Suekuni M, Kokaji Y, Yoshida K, Kiyono T, Kasahara Y, Fujita M. AmNA-Modified Antisense Oligonucleotide Targeting MCM8 as a Cancer-Specific Chemosensitizer for Platinum Compounds. Cancer science, 116:1405-1416, 2025

5. Inoko A, Soga N, Suzuki M, Kiyono T, Ikenouchi J, Kojima T, Sato Y, Saito D, Miyamoto T, Goshima N, Ito H, Kasai K. Long-term expansion of basal cells and the novel differentiation methods identify mechanisms for switching Claudin expression in normal epithelia. Scientific reports, 15:12172, 2025

6. Sekine A, Yasunaga G, Kumamoto S, Fujibayashi S, Munirah I, Bai L, Tani T, Sugano E, Tomita H, Ozaki T, Kiyono T, Inoue-Murayama M, Fukuda T. Characterization of Common Minke Whale (Balaenoptera Acutorostrata) Cell Lines Immortalized with the Expression of Cell Cycle Regulators. Advanced biology, 8:e2300227, 2024

7. Noguchi R, Yoshimatsu Y, Sin Y, Ono T, Tsuchiya R, Yoshida H, Kiyono T, Yonemura Y, Kondo T. Establishment and characterization of NCC-PMP2-C1: a novel patient-derived cell line of pseudomyxoma peritonei with signet ring cells. Human cell, 37:511-522, 2024

8. Bai L, Tani T, Kobayashi T, Nouda R, Kanai Y, Sano Y, Takami K, Tomita H, Sugano E, Ozaki T, Kiyono T, Fukuda T. Establishment of immortalized Egyptian Rousettus bat cell lines. FEBS open bio, 14:598-612, 2024

9. Vachiraarunwong A, Gi M, Kiyono T, Suzuki S, Fujioka M, Qiu G, Guo R, Yamamoto T, Kakehashi A, Shiota M, Wanibuchi H. Characterizing the toxicological responses to inorganic arsenicals and their metabolites in immortalized human bladder epithelial cells. Archives of toxicology, 98:2065-2084, 2024

10. Kanno K, Nakayama K, Razia S, Islam SH, Farzana ZU, Sonia SB, Yamashita H, Ishikawa M, Ishibashi T, Imamura K, Kiyono T, Kyo S. Association between KRAS and PIK3CA Mutations and Progesterone Resistance in Endometriotic Epithelial Cell Line. Current issues in molecular biology, 46:3579-3594, 2024

11. Orimoto A, Addison WN, Mochizuki S, Ariyoshi W, Ono K, Kitamura C, Kiyono T, Fukuda T. Controlled cell proliferation and immortalization of human dental pulp stem cells with a doxycycline-inducible expression system. Cell biochemistry and function, 42:e4064, 2024

12. Yamashita H, Nakayama K, Kanno K, Ishibashi T, Ishikawa M, Iida K, Razia S, Kiyono T, Kyo S. Evaluation of ARID1A as a Potential Biomarker for Predicting Response to Immune Checkpoint Inhibitors in Patients with Endometrial Cancer. Cancers, 16:1999, 2024

13. Orimoto A, Kashiwagi S, Funakoshi A, Shimizu T, Ishii T, Kiyono T, Fukuda T. Transcriptome-wide profiling for melanocytes derived from newborn and adult human epidermis with enhanced proliferation. Cell biology international, 48:1573-1587, 2024

14. Nakahara T, Tabata H, Kato Y, Fuse R, Nakamura M, Yamaji M, Hattori N, Kiyono T, Saito I, Nakanishi T. Construction and Stability of All-in-One Adenovirus Vectors Simultaneously Expressing Four and Eight Multiplex Guide RNAs and Cas9 Nickase. International journal of molecular sciences, 25:8783, 2024

15. Yamamoto G, Tanaka K, Kamata R, Saito H, Yamamori-Morita T, Nakao T, Liu J, Mori S, Yagishita S, Hamada A, Shinno Y, Yoshida T, Horinouchi H, Ohe Y, Watanabe SI, Yatabe Y, Kitai H, Konno S, Kobayashi SS, Ohashi A. WEE1 confers resistance to KRAS(G12C) inhibitors in non-small cell lung cancer. Cancer letters, 611:217414, 2024