Annual Report 2024
Division of Cancer RNA Research
Akihide Yoshimi, Tomoya Muto, Masahiko Ajiro, Asuka Kawachi, Hirotaka Matsui, Ryoichi Maenosono, Rei Kudo, Marimu Sakumoto, Mayumi Hanzawa, Natsuko Shinohara, Michiko Kurikawa, Hirofumi Yamauchi, Takuya Izumi, Mina Yoshida, Moritoshi Sakamoto, Takahiro Nishino, Atsuro Oishi, Satoshi Kaito, Tetsuro Takasaki, Minori Koizumi, Maiko Seki
Introduction
We started our lab on July 1st, 2020, to understand and target aberrant RNA processing in cancers. More specifically, we focus on elucidating the pathogenic roles of RNA binding proteins (RBPs) across cancer, and developing therapeutic approaches including antisense oligonucleotides (ASOs) and mRNA vaccines targeting neoantigens derived from aberrant RNA processing in cancers.
The Team and What We Do
In FY2024, we advanced research on the elucidation of oncogenic mechanisms driven by aberrant RNA splicing in cancer, the development of nucleic acid therapeutics for cancer, large-scale omics analyses using patient cohort data, pathophysiological analyses of hematologic malignancies, and the development of cancer therapeutics targeting GPCRs. Research projects led by Akihide Yoshimi were newly adopted under the AMED Project for Practical Applications of Innovative Cancer Medical Treatments (two projects) and the Program for Supporting Innovative Advanced Research, and these were initiated. These activities were carried out in parallel with ongoing projects from the previous year (including the AMED Platform Project for Supporting Drug Discovery, the AMED Project for Accelerating Next-Generation Cancer Treatment Development, JSPS Challenging Research (Exploratory), and the JST FOREST Program). In addition, we launched one collaborative research project with a pharmaceutical company.
Research Activities
We published five papers and two book chapters. Furthermore, Akihide Yoshimi delivered nine invited lectures, Masahiko Ajiro two, and Tomoya Muto one. Awards included: Akihide Yoshimi, Excellent Award from the Foundation for Biomedical Research and Innovation at Kobe; Ryoichi Maenosono, President’s Award at the 100th Osaka Dialysis Research Meeting, Best Poster Award at the 111th Annual Meeting of the Japanese Urological Association, and the JCA-KFCR Young Investigator Award at the 83rd Annual Meeting of the Japanese Cancer Association; Rena Yoshida, Excellent Award at the 25th Annual Meeting of the RNA Society of Japan and the MBSJ-EMBO Poster Award at the 47th Annual Meeting of the Molecular Biology Society of Japan.
1. Atypical Transcripts: We successfully developed DT finder, a method to detect atypical transcripts (Dark Transcriptome; DT) derived from genomic regions that had been difficult to analyze with conventional technologies, and identified more than 420,000 novel DTs. Notably, we obtained evidence suggesting the immunogenicity of DT-derived peptides. We will continue to focus on the potential of DTs as targets for cancer immunotherapy and biomarkers.
2. Ewing Sarcoma and RNA-Binding Proteins (RBPs): We identified a dependency on RBPs in Ewing sarcoma and developed nucleic acid therapeutics targeting this dependency. Since drug delivery systems (DDS) are critical for nucleic acid therapeutics, we applied machine learning to optimize lipid nanoparticle (LNP) composition successfully. Patent application and manuscript submission are planned within FY2025.
3. hareCLIP-seq: We developed hareCLIP-seq, a novel technique for precise mapping of RBP binding sites on RNA, and obtained insights into new splicing regulatory mechanisms, relationships with RNA modifications, and strategies to improve the efficiency of antisense oligonucleotide (ASO) design. Manuscript submission is planned within FY2025.
4. Bladder Cancer and NECTIN4: NECTIN4-ADC combined with immune checkpoint inhibitors (ICIs) has shown striking clinical efficacy in advanced bladder cancer and has become a standard therapy. However, little is known about the role of NECTIN4 in bladder cancer. By analyzing NGS and spatial profiling data from our established bladder cancer cohort, we elucidated the impact of NECTIN4 on the tumor immune microenvironment. A manuscript will be submitted within FY2025.
5. Hyperprogressive Disease (HPD): We investigated in detail bladder cancer cases that developed hyperprogressive disease (HPD) following ICI therapy. This study provided new insights into the mechanisms of HPD onset, and the findings were reported in npj Precision Oncology.
Education
In 2024, one PhD student from the University of Tokyo, one Master’s student from the University of Tokyo, and one Master’s and one undergraduate students from Kitasato University began their research in our laboratory. Additionally, one PhD student from the University of Tokyo and one PhD student from Jikei University School of Medicine completed their doctoral studies, obtained PhD and graduated.
Akihide Yoshimi continued to serve as Visiting Professor at the Graduate School of Science, Kitasato University, and as Collaborative Professor at Hiroshima University, contributing to education and training. Starting this fiscal year, he was also appointed as Collaborative Professor at Tokyo Medical and Dental University (TMDU) and as Visiting Professor (Graduate School Collaboration) at Keio University School of Medicine. At TMDU, he delivered a lecture in the course Advanced Topics in Disease Life Sciences.
Future Prospects
We successfully developed DT finder to detect atypical transcripts (Dark Transcriptome; DT) derived from genomic regions that had been difficult to analyze with conventional technologies, identifying more than 2,200 novel DTs. Notably, we obtained evidence suggesting that DTs could serve as targets for cancer immunotherapy. Accordingly, in FY2025, we plan to conduct large-scale DT profiling and advance research toward the development of DT-targeted therapies. These projects will be promoted under the One NCC framework, in collaboration with diverse clinical departments, research institutes, EPOC, and resources such as the J-PDX library.
In addition, we aim to complete and publish research initiated in FY2023-2024, including the development of nucleic acid therapeutics for Ewing sarcoma, elucidation of the immunological role of NECTIN4 in bladder cancer, and clarification of novel splicing regulatory mechanisms using the hareCLIP-seq method. Manuscript submissions are planned within FY2025.
List of papers published in 2024
Journal
1. Kusama K, Oishi A, Ueno H, Yoshimi A, Nagase M, Shintake J. Electrically Driven, Bioluminescent Compliant Devices for Soft Robotics. ACS applied materials & interfaces, 17:11248-11258, 2025
2. Iida K, Ajiro M, Nakano-Kobayashi A, Muramoto Y, Takenaga T, Denawa M, Kurosawa R, Noda T, Hagiwara M. Switching of OAS1 splicing isoforms overcomes SNP-derived vulnerability to SARS-CoV-2 infection. BMC biology, 23:60, 2025
3. Izumi-Tamura T, Takano K, Nagao S, Tachi N, Sato S, Nakagawa M, Sone T, Takada K, Ogata H, Saito K, Kato S, Maekawa T, Yoshimi A, Kobayashi S, Kimura F. Proinflammatory and prothrombotic conditions in JAK2V617F-positive MPN: a case of Lemierre's syndrome in essential thrombocythemia. Annals of hematology, 104:2563-2570, 2025
4. Matsui S, Ri C, Bolanos LC, Choi K, Shibamiya A, Ishii A, Takaishi K, Oshima-Hasegawa N, Tsukamoto S, Takeda Y, Mimura N, Yoshimi A, Yokote K, Starczynowski DT, Sakaida E, Muto T. Metabolic reprogramming regulated by TRAF6 contributes to the leukemia progression. Leukemia, 38:1032-1045, 2024
5. Yano N, Chong PF, Kojima KK, Miyoshi T, Luqman-Fatah A, Kimura Y, Kora K, Kayaki T, Maizuru K, Hayashi T, Yokoyama A, Ajiro M, Hagiwara M, Kondo T, Kira R, Takita J, Yoshida T. Long-read sequencing identifies an SVA_D retrotransposon insertion deep within the intron of ATP7A as a novel cause of occipital horn syndrome. Journal of medical genetics, 61:950-958, 2024
6. Mukohyama J, Koizumi M, Yamashita K, Yoshimi A, Shida D, Kakeji Y. Knockdown of CDX2 Induces microRNA-221 Up-regulation in Human Colon Cancer Cells. Anticancer research, 44:3553-3556, 2024
7. Kaito S, Aoyama K, Oshima M, Tsuchiya A, Miyota M, Yamashita M, Koide S, Nakajima-Takagi Y, Kozuka-Hata H, Oyama M, Yogo T, Yabushita T, Ito R, Ueno M, Hirao A, Tohyama K, Li C, Kawabata KC, Yamaguchi K, Furukawa Y, Kosako H, Yoshimi A, Goyama S, Nannya Y, Ogawa S, Agger K, Helin K, Yamazaki S, Koseki H, Doki N, Harada Y, Harada H, Nishiyama A, Nakanishi M, Iwama A. Inhibition of TOPORS ubiquitin ligase augments the efficacy of DNA hypomethylating agents through DNMT1 stabilization. Nature communications, 15:7359, 2024
8. Nishimura K, Takahara K, Komura K, Ishida M, Hirosuna K, Maenosono R, Ajiro M, Sakamoto M, Iwatsuki K, Nakajima Y, Tsujino T, Taniguchi K, Tanaka T, Inamoto T, Hirose Y, Ono F, Kondo Y, Yoshimi A, Azuma H. Mechanistic insights into lethal hyper progressive disease induced by PD-L1 inhibitor in metastatic urothelial carcinoma. NPJ precision oncology, 8:206, 2024
9. Jin Q, Harris E, Myers JA, Mehmood R, Cotton A, Shirnekhi HK, Baggett DW, Wen JQ, Schild AB, Bhansali RS, Klein J, Narina S, Pieters T, Yoshimi A, Pruett-Miller SM, Kriwacki R, Abdel-Wahab O, Malinge S, Ntziachristos P, Obeng EA, Crispino JD. Disruption of cotranscriptional splicing suggests RBM39 is a therapeutic target in acute lymphoblastic leukemia. Blood, 144:2417-2431, 2024
10. Kudo R, Safonov A, Jones C, Moiso E, Dry JR, Shao H, Nag S, da Silva EM, Yildirim SY, Li Q, O'Connell E, Patel P, Will M, Fushimi A, Benitez M, Bradic M, Fan L, Nakshatri H, Sudhan DR, Denz CR, Huerga Sanchez I, Reis-Filho JS, Goel S, Koff A, Weigelt B, Khan QJ, Razavi P, Chandarlapaty S. Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion. Cancer cell, 42:1919-1935.e9, 2024