Comprehensive understanding and novel therapeutic approaches for spliceosome mutant cancers

• Project/Area Number: 21H04828
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: National Cancer Center Japan
• Principal Investigator: 吉見 昭秀 国立研究開発法人国立がん研究センター, 研究所, 分野長 (80609016)
• Project Period (FY): 2021-04-05 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥42,250,000 (Direct Cost: ¥32,500,000、Indirect Cost: ¥9,750,000); Fiscal Year 2023: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2022: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2021: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000)
• Keywords: RNA splicing / Cancer / 核酸医薬 / Multi-omics analysis / Bladder carcinoma / ASO / がん / RNAスプライシング / 腫瘍生物学 / 白血病 / Thymoma / Leukemia / RNA binding protein / スプライシング / 神経膠腫 / RNA結合蛋白質

Outline of Research at the Start

様々ながんにおいてRNAスプライシング因子の遺伝子変異（以下スプライシング変異）が高頻度に認められることが2011年に発見され、スプライシング変異は発がんにおいて重要な役割を果たしていることが示唆された。ところが、スプライシング変異による発がんの仕組みの解明や、スプライシング変異をもつがんに対する治療法の開発はあまり進んでいない。本研究ではスプライシング変異による発がんの仕組みを様々な角度から多面的に検討し、それを有機的かつ効率的に統合して解釈することによって、がんにおけるRNAスプライシング異常による発がんメカニズムを理解し、治療標的を探索することを目的とする。

Outline of Annual Research Achievements

本研究では、最先端のsplicing解析技術をがん横断的に用いることにより、各種のがんにおけるゲノム、遺伝子発現、splicingの多層的な異常をOmics解析で同定することを試みた。特に、膀胱がんにおけるOmics解析では、470例の患者検体のWhole genome sequence/Exome sequence/RNA sequenceおよびTissue microarrayを用いた41種類の抗原による免疫多重染色により包括的なデータセットが本研究により完成し、詳細な臨床情報に紐づいた様々な角度からの研究が可能となった。特に、ゲノム・transcriptome異常が腫瘍免疫微小環境に与える影響を解明するとともに、臨床的意義のあるバイオマーカーを同定することに成功した（Molecular Cancer 2023; Cancer Science 2023; いずれもcorresponding author）。また、RNA sequenceデータのみからsplicing-associated variant(SAV)を同定するpipelineを開発し、23万件以上に及ぶRNA sequenceデータの解析を元に、多数の病的意義のある新規SAVを同定した(Nature Communications 2022; last author)。なかでもがんにおいてはTP53遺伝子におけるSAVが最も高頻度（約3.0%）に見られることが判明し、antisense oligonucleotide (ASO)の標的配列やdrug delivery system (DDS) の最適化を通して、TP53異常を有するがんを標的とする新規治療法を開発することに成功した。

Research Progress Status

令和5年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和5年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center/New York University/Columbia University(米国)
• [Int'l Joint Research] Ghent University(ベルギー)
• [Int'l Joint Research] Shandong University/Beijing Institute of Genomics(中国)
• [Int'l Joint Research] Simon Fraiser University(カナダ)
• [Int'l Joint Research] Northern University(クロアチア)
• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center/Columbia University/New York University(米国)
• [Int'l Joint Research] Ghent University(ベルギー)
• [Int'l Joint Research] Shangond University(中国)
• [Int'l Joint Research] Northern University(クロアチア)
• [Int'l Joint Research] Simon Fraiser University(カナダ)
• [Int'l Joint Research]
• [Journal Article] The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer (2023)
  • Author(s): Komura K, Hirosuna K, Tokushige S, Nishimura K, Ishida M, Hayashi T, Ura A, Ohno T, Yamazaki S, Nakamori K, Kinoshita S, Tsujino T, Maenosono R, Ajiro M, Yoshikawa Y, Takai T, Tsutsumi T, Taniguchi K, Tanaka T, Takahara K, Konuma T, Inamoto T, Hirose Y, Ono F, Shiraishi Y, Yoshimi A#, Azuma H.
  • Journal Title: Molecular Cancer Volume: 22 Issue: 1 Pages: 185-185
  • DOI: 10.1186/s12943-023-01897-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer (2023)
  • Author(s): 2.Ma HL, Bizet M, Da Costa CS, Murisier F, de Bony EJ, Wang MK, Yoshimi A, Lin KT, Riching KM, Caine E, Wang X, Beckman JI, Arya S, Droin N, Calonne E, Hassabi B, Zhang QY, Li A, Putmans A, Malbec L, Hubert C, Lan J, Mies F, Yang Y, Solary E, Daniels D, Gupta YK, Deplus R, Abdel-Wahab O, Yang YG, Fuks F
  • Journal Title: Molecular Cell Volume: 83 Issue: 23 Pages: 4239-4254.e10
  • DOI: 10.1016/j.molcel.2023.11.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Tertiary lymphoid structure and neutrophil?lymphocyte ratio coordinately predict outcome of pembrolizumab (2023)
  • Author(s): Komura K,Tokushige S, Ishida M, Hirosuna K,Yamazaki S,Nishimura K,Ajiro M,Ohno T,Nakamori K,Kinoshita S,Tsujino T, Maenosono R,Yoshikawa Y, Takai T, Tsutsumi T,Taniguchi K,Tanaka T,Takahara K, Inamoto T,Hirose Y, Ono F,Shiraishi Y,Yoshimi A,Azuma H.
  • Journal Title: Cancer Science Volume: 114 Issue: 12 Pages: 4622-31
  • DOI: 10.1111/cas.15976
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RNA splicing dysregulation in hematological malignancies (2023)
  • Author(s): 吉田 澪奈、山内 浩文、佐久本 真梨夢、吉見 昭秀
  • Journal Title: Rinsho Ketsueki Volume: 64 Issue: 7 Pages: 646-653
  • DOI: 10.11406/rinketsu.64.646
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress (2023)
  • Author(s): Igarashi Taichi、Mazevet Marianne、Yasuhara Takaaki、Yano Kimiyoshi、Mochizuki Akifumi、Nishino Makoto、Yoshida Tatsuya、Yoshida Yukihiro、Takamatsu Nobuhiko、Yoshimi Akihide、Shiraishi Kouya、Horinouchi Hidehito、Kohno Takashi、Hamamoto Ryuji、Adachi Jun、Zou Lee、Shiotani Bunsyo
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 4991-4991
  • DOI: 10.1038/s41467-023-40578-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Systematic identification of intron retention associated variants from massive publicly available transcriptome sequencing data (2022)
  • Author(s): Shiraishi Yuichi、Okada Ai、Chiba Kenichi、Kawachi Asuka、Omori Ikuko、Mateos Ra?l Nicol?s、Iida Naoko、Yamauchi Hirofumi、Kosaki Kenjiro、Yoshimi Akihide
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 5357-5357
  • DOI: 10.1038/s41467-022-32887-9
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenic Roles of RNA-Binding Proteins in Sarcomas (2022)
  • Author(s): Hai Yu、Kawachi Asuka、He Xiaodong、Yoshimi Akihide
  • Journal Title: Cancers Volume: 14 Issue: 15 Pages: 3812-3812
  • DOI: 10.3390/cancers14153812
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural basis of cytokine-mediated activation of ALK family receptors (2021)
  • Author(s): De Munck Steven、Provost Mathias、Kurikawa Michiko、Omori Ikuko、Mukohyama Junko、Felix Jan、Bloch Yehudi、Abdel-Wahab Omar、Bazan J. Fernando、Yoshimi Akihide、Savvides Savvas N.
  • Journal Title: Nature Volume: 600 Issue: 7887 Pages: 143-147
  • DOI: 10.1038/s41586-021-03959-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Efficient production of human neutrophils from iPSCs that prevent murine lethal infection with immune cell recruitment. (2021)
  • Author(s): Miyauchi M, Ito Y, Nakahara F, Hino T, Nakamura F, Iwasaki Y, Kawagoshi T, Koya J, Yoshimi A, Arai S, Kagoya Y, Kurokawa M
  • Journal Title: Blood Volume: 138 Issue: 24 Pages: 2555-2569
  • DOI: 10.1182/blood.2021011576
  • Peer Reviewed
• [Journal Article] Loss-of-function mutations in BCOR contribute to chemotherapy resistance in acute myeloid leukemia. (2021)
  • Author(s): Honda A, Koya J, Yoshimi A, Miyauchi M, Taoka K, Kataoka K, Arai S, Kurokawa M.
  • Journal Title: Experimental Hematology Volume: - Pages: 42-48.e11
  • DOI: 10.1016/j.exphem.2021.07.005
  • Peer Reviewed
• [Journal Article] Physical interaction between BAALC and DBN1 induces chemoresistance in leukemia (2021)
  • Author(s): Maki Hiroaki、Yoshimi Akihide、Shimada Takashi、Arai Shunya、Morita Ken、Kamikubo Yasuhiko、 Ikegawa Masaya、Kurokawa Mineo
  • Journal Title: Experimental Hematology Volume: 94 Pages: 31-36
  • DOI: 10.1016/j.exphem.2020.12.003
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant RNA splicing and therapeutic opportunities in cancers (2021)
  • Author(s): Yamauchi Hirofumi、Nishimura Kazuki、Yoshimi Akihide
  • Journal Title: Cancer Science Volume: 113 Issue: 2 Pages: 373-381
  • DOI: 10.1111/cas.15213
  • Peer Reviewed
• [Presentation] A multi-omics analysis revealed NECTIN4 as a potential predictive marker of precision therapy in bladder cancer. (2023)
  • Author(s): Nishimura K, Komura K, Hirosuna K, Ishida M, Inamoto T, Azuma H, Yoshimi A
  • Organizer: The 3rd International Congress of the Asian Oncology Society
  • Int'l Joint Research
• [Presentation] Pre-clinical study of a novel spliceosomel inhibitor. (2023)
  • Author(s): Yoshimi A
  • Organizer: The 61st Annual Meeting of Japan Society of Clinical Oncology
  • Invited
• [Presentation] Mechanistic insight of deadly hyper progressive disease caused by checkpoint inhibitor in metastatic urothelial carcinoma (2023)
  • Author(s): Nishimura K, Komura K, Ishida M, Hirosuna K, Inamoto T, Yoshimi A, Azuma H.
  • Organizer: The 61st Annual Meeting of Japan Society of Clinical Oncology
• [Presentation] Comprehensive analysis of the tumor microenvironment in bladder cancer with FGFR3 alterations (2023)
  • Author(s): Komura K, Hirosuna K, Shiraishi Y, Yoshimi A, Azuma H
  • Organizer: The 61st Annual Meeting of Japan Society of Clinical Oncology
• [Presentation] Targeting Aberrant RNA Splicing in Cancer. (2023)
  • Author(s): Yoshimi A
  • Organizer: JCA-AACR Joint Symposia
  • Int'l Joint Research / Invited
• [Presentation] A multi-omics analysis revealed NECTIN4 as a potential predictive marker of precision therapy in bladder cancer (2023)
  • Author(s): 西村一希、小村和正、廣砂賢祐、石田光明、稲元輝生、東治人、吉見昭秀
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] Pathogenic roles of splicing factor mutations in myeloid leukemia. (2023)
  • Author(s): 吉見昭秀
  • Organizer: 第82回日本癌学会学術集会
  • Invited
• [Presentation] Cancer immunotherapy targeting aberrant RNA splicing regulation (2023)
  • Author(s): Ajiro M, Matsushima S, Iida K, Nishimura K, Komura K, Azuma H, Hagiwara M, Yoshimi A
  • Organizer: The 82nd Annual Meeting of the Japanese Cancer Association
• [Presentation] A comprehensive multi-omics analysis exploring the correlation between NECTIN4 and tumor microenvironment profiles in bladder cancer. (2023)
  • Author(s): Nishimura K, Komura K, Hirosuna K, Ishida M, Inamoto T, Azuma H, Yoshimi A.
  • Organizer: 2023 ASCO Breakthrough
  • Int'l Joint Research
• [Presentation] Investigation of dysregulated RNA splicing for cancer immunity (2023)
  • Author(s): Ajiro M, Matsushima S, Iida K, Nishimura K, Komura K, Azuma H, Hagiwara M, Yoshimi A.
  • Organizer: 第 24 回 日本RNA 学会年会
• [Presentation] Nucleic Acid Therapeutics for Cancers with Intron-associated Variants. (2023)
  • Author(s): Yoshida M, Ailiken G, Muto T, Yagishita S, Go A, Yamauchi H, Sakumoto M, Hanzawa M, Shinohara N, Kurikawa M, Kawachi A, Ajiro M, Shiraishi Y, Matsui H, Kamiya Y, Asanuma H, Hamada A, Yoshimi A
  • Organizer: 第 24 回 日本RNA 学会年会
• [Presentation] Targeting Cis- and Trans-regulations of Pre-mRNA Splicing in Cancer (2023)
  • Author(s): Yoshimi A
  • Organizer: 2nd JCA-AACR Precision Cancer Medicine International Conference
  • Int'l Joint Research / Invited
• [Presentation] Elevation of plasma interleukin-8 caused by checkpoint inhibitor could evoke deadly hyper-progressive disease in metastatic urothelial carcinoma (2023)
  • Author(s): 西村一希、小村和正、石田光明、稲元輝生、吉見昭秀、東治人
  • Organizer: 第110回日本泌尿器科学会総会
• [Presentation] RNAスプライシング異常からがんを理解する (2023)
  • Author(s): 吉見昭秀
  • Organizer: 第3回SAMURAI研究会
  • Invited
• [Presentation] がんのスプライシング異常を標的とした治療法探索 (2023)
  • Author(s): 吉見昭秀
  • Organizer: 第47回セルセラピーセミナー
  • Invited
• [Presentation] がんにおけるRNA生物学の理解と治療法の探索 (2023)
  • Author(s): 吉見昭秀
  • Organizer: 第70回よこはまNMR研究会
  • Invited
• [Presentation] RNAスプライシング異常を標的としたがん治療法 (2023)
  • Author(s): 吉見昭秀
  • Organizer: 超異分野学会東京大会2023基調講演
  • Invited
• [Presentation] Targeting Splicing-Associated Variants in Leukemias (2023)
  • Author(s): 吉見昭秀
  • Organizer: 2023 Normal/Malignant Hematopoiesis and Novel Therapies for Hematologic Malignancies Symposium
  • Int'l Joint Research / Invited
• [Presentation] RNAスプライシング異常からがんを理解する (2022)
  • Author(s): 吉見昭秀
  • Organizer: MSD Urology Seminar
  • Invited
• [Presentation] RNAスプライシング異常を標的にした治療戦略 (2022)
  • Author(s): 吉見昭秀
  • Organizer: 第10回Cancer Stem Cell Symposium
  • Invited
• [Presentation] がんのRNAスプライシング異常 (2022)
  • Author(s): 吉見昭秀
  • Organizer: 第一三共株式会社オンコロジー研究所セミナー
  • Invited
• [Presentation] 遺伝子変異に起因する RNA スプライシング異常から紐解く発がんメカニズム (2022)
  • Author(s): 吉見昭秀
  • Organizer: 第51回日本環境変異原ゲノム学会年次大会シンポジウム
  • Invited
• [Presentation] がんのRNAスプライシング異常 (2022)
  • Author(s): 吉見昭秀
  • Organizer: 愛知県がんセンター研究所招聘セミナー
  • Invited
• [Presentation] Aberrant RNA splicing in hematologic malignancies (2022)
  • Author(s): 吉見昭秀
  • Organizer: The 84th Japanese Society of Hematology Annual Meeting Symposium
  • Invited
• [Presentation] 次世代核酸医薬による新規がん治療法の展開 (2022)
  • Author(s): 吉見昭秀
  • Organizer: BioJapan 2022
• [Presentation] RNAスプライシング異常から理解するがんの病態と治療法の開発 (2022)
  • Author(s): 吉見昭秀
  • Organizer: 第159回小児血液・腫瘍・免疫懇話会特別講演会
  • Invited
• [Presentation] Understanding and Targeting Aberrant RNA Splicing in Leukemias (2022)
  • Author(s): 吉見昭秀
  • Organizer: The 8th Canadian Conference on Epigenetics
  • Int'l Joint Research / Invited
• [Presentation] 白血病におけるスプライシング異常による病態理解と治療法開発 (2022)
  • Author(s): 吉見昭秀
  • Organizer: 第81回日本癌学会学術総会モーニングレクチャー
  • Invited
• [Presentation] Understanding and Targeting Aberrant RNA Splicing in Leukemias (2022)
  • Author(s): 吉見昭秀
  • Organizer: 第81回日本癌学会学術総会 JCA-Mauveynay Award Seminar
  • Invited
• [Presentation] Coordinated Alterations in RNA Splicing and Epigenome in Cancers (2022)
  • Author(s): 吉見昭秀
  • Organizer: 第81回日本癌学会学術総会 International session
  • Invited
• [Presentation] Aberrant RNA Splicing and Alterations in Epigenome Coordinately Drive Tumorigenesis (2022)
  • Author(s): 吉見昭秀
  • Organizer: 第23回日本RNA学会年会
• [Presentation] 造血器腫瘍のRNAスプライシングスプライシング異常を起点にした治療法 (2022)
  • Author(s): 吉見昭秀
  • Organizer: 第17回北関東小児セミナー
  • Invited
• [Presentation] がん横断的解析から理解するスプライシング異常 (2022)
  • Author(s): 吉見昭秀
  • Organizer: 令和3年度国際がん研究シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] Understanding and Targeting Aberrant Splicing in Leukemias (2022)
  • Author(s): Yoshimi A
  • Organizer: 4.The 1st JCA-AACR Precision Cancer Medicine International Conference
  • Int'l Joint Research / Invited
• [Presentation] がん横断的解析から理解するスプライシング異常 (2022)
  • Author(s): Yoshimi A
  • Organizer: 令和3年度国際がん研究シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] Understanding and Targeting Aberrant Splicing in Cancers (2021)
  • Author(s): Yoshimi A
  • Organizer: 5.The 39th Sapporo International Cancer Symposium
  • Int'l Joint Research / Invited
• [Presentation] 米国東海岸留学のすすめ (2021)
  • Author(s): 吉見昭秀
  • Organizer: 日本分子生物学会年会
  • Invited
• [Presentation] Healthcare workers’ attitudes toward COVID-19 mRNA vaccine technology: a nation-wide cross-sectional survey from Croatia (2021)
  • Author(s): Tomislav Mestrovic, Simona Hren, Chirag Raval, Xiaodong He, Akihide Yoshimi
  • Organizer: The 19th International mRNA Health Conference 2021
  • Int'l Joint Research
• [Presentation] Mutations in the RNA Splicing Factor SF3B1 Target PPP2R5A to Promote Tumorigenesis through MYC Stabilization (2021)
  • Author(s): Hirofumi Yamauchi, Zhaoqi Liu, Michiko Kurikawa, Ikuko Omori, Xiaohui Song, Hanako Nakamura, Hana Cho, Lillian Bitner, Bo Liu, Atsuro Oishi, Anthony R. Mato, Peter Ruvolo, Giulia Fabbri, Laura Pasqualucci, Omar Abdel-Wahab, Raul Rabadan, Akihide Yoshimi
  • Organizer: The 39th Sapporo International Cancer Symposium
  • Int'l Joint Research
• [Presentation] Mutant IDH1 promotes aberrant splicing in gliomas (2021)
  • Author(s): Michiko Kuirkawa, Kuan-Ting Lin, Takaki Omura, Ikuko Omori, Hirofumi Yamauchi, Hanako Nakamura, Xiaohui Song, Atsuro Oishi, Adrian R. Krainer, Yoshitaka Narita, Akihide Yoshimi
  • Organizer: The 39th Sapporo International Cancer Symposium
  • Int'l Joint Research
• [Book] 核酸医薬 (2024)
  • Author(s): 吉見昭秀
  • Total Pages: 500
  • Publisher: NTS
• [Book] 実験医学2023年8月号「がん治療標的の新星 スプライシング異常」 (2023)
  • Author(s): 吉見昭秀
  • Total Pages: 150
  • Publisher: 羊土社
• [Book] mRNAの制御機構の解明と治療薬・ワクチンへの活用 (2023)
  • Author(s): 西野貴大, 網代将彦, 吉見昭秀
  • Total Pages: 411
  • Publisher: 技術情報協会
  • ISBN: 9784861049378
• [Book] RNA Therapeutics for Cancers (2022)
  • Author(s): Michiko Kurikawa, Marimu Sakumoto and Akihide Yoshimi
  • Total Pages: 24
  • Publisher: IntechOpen
• [Remarks] 膀胱がんの FGFR3 異常が腫瘍免疫微小環境と免疫療法の効果に与える影響を解明
  • URL: https://www.ncc.go.jp/jp/information/pr_release/2023/1208/index.html
• [Remarks] 「生命現象の多様性を支えるRNAスプライシングの仕組みを探る」
  • URL: https://indd.adobe.com/view/6e1dac25-08ef-48ca-8420-832cb3d89c73?startpage=2
• [Remarks] がんRNA研究分野
  • URL: https://www.ncc.go.jp/jp/ri/division/cancer_rna/index.html
• [Remarks] 大規模公共トランスクリプトームデータを活用した疾患関連変異の新規スクリーニング手法の開発
  • URL: https://www.ncc.go.jp/jp/information/pr_release/2022/0929/index.html
• [Remarks] 吉見昭秀が「ASH Global Research Award 2022」を受賞
  • URL: https://www.ncc.go.jp/jp/topics/2022/0804/index.html
• [Remarks] 国がん吉見氏、創薬応用も視野にがんのスプライシング異常を研究中
  • URL: https://bio.nikkeibp.co.jp/atcl/news/p1/22/05/09/09452/
• [Remarks] がん細胞の増殖に重要な役割を果たすALK受容体の構造を解明新しい治療法開発に期待
  • URL: https://www.ncc.go.jp/jp/information/pr_release/2021/1014/index.html
• [Remarks] Breakthrough Discovery on the Structure of ALK
  • URL: https://www.ncc.go.jp/en/information/press_release/20211014/index.html
• [Remarks] 3D structure of cell receptor with critical role
  • URL: https://vib.be/news/revealed-3d-structure-cell-receptor-critical-role-health-and-disease