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Identification of regulatory components of Wnt signaling in beta-catenin and T-cell factor-4 transcriptional complex as therapeutic targets for colorectal cancer

Research Project

Project/Area Number 17H03603
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor therapeutics
Research InstitutionNational Cancer Center Japan

Principal Investigator

Masuda Mari  国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (70435717)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2019: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2018: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
Fiscal Year 2017: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
KeywordsWntシグナル / TCF4/β-catenin 転写複合体 / プロテオーム解析 / 大腸がん / 治療標的 / がん幹細胞 / Wnt シグナル / TCF4 / β-catenin / 転写複合体 / 分子標的治療薬 / トランスレーショナルリサーチ / 細胞・組織 / 癌 / 発現制御 / シグナル伝達
Outline of Final Research Achievements

Constitutive activation of Wnt signaling is observed in most colorectal cancers (CRCs) and has been believed to play a pivotal role in maintaining cancer stem cells. Through the screening with a siRNA library targeting 70 molecules previously identified as components of the TCF4/β-catenin transcriptional complex, we have explored their regulatory effects on the Wnt signaling. We looked at the expression of Wnt target genes such as c-Myc and Axin, cell proliferation, and Wnt signaling activities in colorectal cancer spheroids by WASA (Wnt signaling Activity in Spheroid Assay) method we developed. As a result, we identified several molecules as candidates for therapeutic targets for CRCs. Of interest, most of the candidate molecules were involved in DNA damage and transcription-coupled DNA repair.

Academic Significance and Societal Importance of the Research Achievements

Wntシグナルの最下流にあるTCF4/β-catenin 転写複合体の制御の全貌を解明することは、多くの生物種において保持されているWntシグナルの機能とその分子機構を理解するうえで学術的意義が高い。一方、Wntシグナルの恒常的活性化は大腸がんをはじめとする様々ながんで報告されており、本シグナル経路に依存する発がんやがん幹細胞の維持に関わる分子機構を理解することによって、新規治療標的の同定に繋がることが期待される。本研究成果は、Wntシグナルの活性化がドライバーとなる様々ながん種に対し新たな治療薬を創出する土台を構築するもので、社会への貢献度が高く重要な意義がある。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (39 results)

All 2020 2019 2018 2017 Other

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (26 results) (of which Int'l Joint Research: 16 results,  Invited: 9 results) Book (3 results) Remarks (2 results)

  • [Journal Article] Feasibility of Targeting Traf2-and-Nck-Interacting Kinase in Synovial Sarcoma2020

    • Author(s)
      Sekita Tetsuya、Yamada Tesshi、Kobayashi Eisuke、Yoshida Akihiko、Hirozane Toru、Kawai Akira、Uno Yuko、Moriyama Hideki、Sawa Masaaki、Nagakawa Yuichi、Tsuchida Akihiko、Matsumoto Morio、Nakamura Masaya、Nakayama Robert、Masuda Mari
    • Journal Title

      Cancers

      Volume: 12 Issue: 5 Pages: 1258-1258

    • DOI

      10.3390/cancers12051258

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence2020

    • Author(s)
      Miyanaga Akihiko、Masuda Mari、Motoi Noriko、Tsuta Koji、Nakamura Yuka、Nishijima Nobuhiko、Watanabe Shun-ichi、Asamura Hisao、Tsuchida Akihiko、Seike Masahiro、Gemma Akihiko、Yamada Tesshi
    • Journal Title

      Lung Cancer

      Volume: 145 Pages: 85-94

    • DOI

      10.1016/j.lungcan.2020.03.027

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prognostic impact of ACTN4 gene copy number alteration in hormone receptor-positive, HER2-negative, node-negative invasive breast carcinoma2020

    • Author(s)
      Sugano T, Yoshida M, Masuda M, Ono M, Tamura K, Kinoshita T, Tsuda H, Honda K, Gemma A, Yamada T
    • Journal Title

      Br J Cancer.

      Volume: 122 Issue: 12 Pages: 1811-1817

    • DOI

      10.1038/s41416-020-0821-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Utility of Reverse-Phase Protein Array for Refining Precision Oncology2019

    • Author(s)
      Masuda M, Yamada T
    • Journal Title

      Adv Exp Med Biol.

      Volume: 1188 Pages: 239-249

    • DOI

      10.1007/978-981-32-9755-5_13

    • ISBN
      9789813297548, 9789813297555
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hunting hidden pieces of signaling pathways in hepatocellular carcinoma.2019

    • Author(s)
      Masuda M.
    • Journal Title

      HepatoBiliary Surg Nutr.

      Volume: 1 Issue: 1 Pages: 74-76

    • DOI

      10.21037/hbsn.2018.10.10

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Signaling pathway profiling using reverse-phase protein array and its clinical applications2017

    • Author(s)
      Masuda Mari、Yamada Tesshi
    • Journal Title

      Expert Review of Proteomics

      Volume: 14 Issue: 7 Pages: 607-615

    • DOI

      10.1080/14789450.2017.1344101

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The emergence of TNIK as a therapeutic target for colorectal cancer.2017

    • Author(s)
      Masuda M, Yamada T.
    • Journal Title

      Expert Opin Ther Targets.

      Volume: 4 Issue: 4 Pages: 353-355

    • DOI

      10.1080/14728222.2017.1297799

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The emergence of TNIK inhibitors in cancer therapeutics.2017

    • Author(s)
      Yamada T, Masuda M.
    • Journal Title

      Cancer Sci.

      Volume: 印刷中 Issue: 5 Pages: 818-823

    • DOI

      10.1111/cas.13203

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Wntシグナルを標的とした大腸がん治療薬の開発及びその適応拡大の可能性2020

    • Author(s)
      増田万里
    • Organizer
      御茶ノ水がん学アカデミア第160回集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Application of the TNIK inhibitor, NCB-0846, to Colorectal Cancer Treatment and Beyond2019

    • Author(s)
      Masuda Mari
    • Organizer
      8th Grobal Reverse Phase Phase Protein Array Workshop
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] TNIK阻害剤のapoptosis誘導機序の解明2019

    • Author(s)
      増田万里
    • Organizer
      第15回日本臨床プロテオゲノミクス研究
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Utility of Reverse-Phase Protein Array for Proteogenomic Analysis2019

    • Author(s)
      Masuda Mari
    • Organizer
      Tokyo Cancer Moonshot Workshop
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Elucidation of Mechanism of Actions Leading to Apoptosis in Colorectal Cancer Cells Induced by NCB-08462019

    • Author(s)
      Masuda M., Goto N., Uno Y., Moriyama H., Sekita T., Sawa M., Yamada T.
    • Organizer
      第 78 回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 滑膜肉腫に対するTNIK阻害剤の有効性2019

    • Author(s)
      関田哲也、山田哲司、後藤尚子、弘實透、小林英介、川井章、松本守雄、中村雅也、中山ロバート、増田万里
    • Organizer
      第39回 日本分子腫瘍マーカー研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 大腸がん幹細胞の遺伝子転写を標的とした新規分子標的治療薬の開発.2019

    • Author(s)
      増田万里、弘實透、宇野佑子、澤匡明、山田哲司.
    • Organizer
      第14回日本がん分子標的治療学会・TRワークショップ
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Application of the TNIK inhibitor, NCB-0846, to colorectal cancer treatment and beyond.2019

    • Author(s)
      Mari Masuda
    • Organizer
      8th Global Reverse Phase Protein Array Workshop,
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Traf2-and Nck-interacting kinase (TNIK) inhibitor, NCB-0846, suppresses TGF-β1-induced epithelial-mesenchymal transition in lung cancer.2018

    • Author(s)
      T. Sugano, M. Masuda, Y. Uno, N. Goto, M. Seike, M. Sawa, A. Gemma, T. Yamada.
    • Organizer
      AACR Annual meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] TRAF2 and NCK-interacting protein kinase (TNIK) regulates cancer stemness and adipogenesis of osteosarcoma cells.2018

    • Author(s)
      T. Hirozane, M. Masuda, N. Goto, T. Sugano, N. Asano, E. Kobayashi, K. Horiuchi, H. Morioka, A. Kawai, M. Sawa, M. Matsumoto, M. Nakamura, T. Yamada.
    • Organizer
      AACR Annual meeting 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 肉腫のプロテオゲノミクス解析:国際がんプロテオゲノミクスコンソーシアム(ICPC).2018

    • Author(s)
      近藤格、服部恵美、塩澤久美子、尾野雅哉、増田万里、山田哲司.
    • Organizer
      第14 日本臨床プロテオゲノミクス研究会.
    • Related Report
      2018 Annual Research Report
  • [Presentation] 肉腫のプロテオゲノミクス解析:国際がんプロテオゲノミクスコンソーシアム(ICPC).2018

    • Author(s)
      近藤格、服部恵美、尾野雅哉、増田万里、川井章、山田哲司.
    • Organizer
      日本質量分析学会・日本プロテオーム学会2018年合同大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] TNIK is a novel molecular target for osteosarcoma treatment and controls osteosarcoma cell fate.2018

    • Author(s)
      Toru Hirozane, Mari Masuda, Naoko Goto, Teppei Sugano, Naofumi Asano, Eisuke Kobayashi, Akira Kawai, Keisuke Horiuchi, Morio Matsumoto, Masaya Nakamura, Masaaki Sawa, Hideo Morioka, Tesshi Yamada.
    • Organizer
      2018 CTOS Annual Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Clarification of the Signaling Network Affected by the TNIK Inhibitor, NCB-0846, Using Reverse-phase Protein Array.2018

    • Author(s)
      Mari Masuda, Takeomi Inoue, Yuko Uno, Naoko Goto, Masaaki Sawa and Tesshi Yamada.
    • Organizer
      The Human Proteome Organization (HUPO) 2018 meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 網羅的ゲノム解析を用いた肺カルチノイドの新規治療標的遺伝子の同定.2018

    • Author(s)
      宮永晃彦、増田万里、蔦幸治、西島伸彦、清家正博、浅村尚生、弦間昭彦、山田哲司.
    • Organizer
      第59回日本肺癌学会学術総会,
    • Related Report
      2018 Annual Research Report
  • [Presentation] Application of Proteomic Technology in Development of Novel TNIK Inhibitor Blocking Wnt Signaling2017

    • Author(s)
      Mari Masuda, Yuko Uno, Shigeki Kashimoto, Hideki Moriyama, Masaaki Sawa and Tesshi Yamada
    • Organizer
      日本プロテオーム学会2017年大会JHUPO第15回大会
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Preclinical development of NCB-0846, a novel TNIK inhibitor that blocks Wnt signaling in colorectal cancer2017

    • Author(s)
      Mari Masuda, Takeomi Inoue, Yuko Uno, Hideki Moriyama, Shigeki Kashimoto, Naoko Goto, Masaki Sawa and Tesshi Yamada
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 新規TNIK 阻害薬によるEMT 制御2017

    • Author(s)
      菅野哲平、増田万里、宇野佑子、森山英樹、後藤尚子、清家正博、澤匡明、弦間昭彦、山田哲司
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] TNIK は骨肉腫の新規治療標的となりうる2017

    • Author(s)
      弘實透、増田万里、後藤尚子、浅野尚文、小林英介、川井章、堀内圭輔、澤匡明、山田哲司
    • Organizer
      第76回日本癌学会月術総会
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] TNIK 阻害剤はWnt シグナルを減弱させてがん幹細胞画分を減少させる2017

    • Author(s)
      宇野佑子、増田万里、森山英樹、澤匡明、山田哲司
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] TRAF2 and NCK-interacting protein kinase(TNIK)は骨肉腫の分子標的となりうる2017

    • Author(s)
      弘實透,増田万里,浅野尚文,小林英介,川井章,堀内圭輔,松本守雄,澤匡明,森岡秀夫,中村雅也,山田哲司
    • Organizer
      日本整形外科学会基礎学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 骨肉腫治療におけるTNIK阻害剤の可能性2017

    • Author(s)
      弘實 透,増田万里,後藤尚子,菅野哲平,浅野尚文,小林英介,川井 章,堀内圭輔,松本守雄,中村雅也,澤 匡明,森岡秀夫,山田 哲司
    • Organizer
      分子腫瘍マーカー研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] A novel TNIK inhibitor potently downregulates cancer stem cell population through attenuation of Wnt signaling2017

    • Author(s)
      Yuko Uno, Hideki Moriyama, Shigeki Kashimoto, Mari Masuda, Masaaki Sawa, Tesshi Yamada
    • Organizer
      AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elucidation of Signaling Pathways Affected by TNIK Inhibitor, NCB-0846, Using Reverse-Phase Protein Array2017

    • Author(s)
      Mari Masuda, Takeomi Inoue, Yuko Uno, Masaaki Sawa and Tesshi Yamada
    • Organizer
      RPPA Global Workshop 2017 Dublin
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] がん高精度医療における逆相タンパクアレイ基盤の有用性2017

    • Author(s)
      増田万里
    • Organizer
      北里疾患プロテオーム研究会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Therapeutic target discovery by cancer proteomics in the era of large-scale genome-resequencing2017

    • Author(s)
      Tesshi Yamada and Mari Masuda
    • Organizer
      HUPO 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Book] Chapter 10. Biomarkers of Lung Cancer: Liquid Biopsy Comes of Age. Biomarkers in Cancer Therapy.2019

    • Author(s)
      Miyanaga A., Masuda M., Yamada T.
    • Total Pages
      5
    • Publisher
      Springer Nature
    • Related Report
      2018 Annual Research Report
  • [Book] Chapter 15. Utility of Reverse-phase Protein Array for Refining Precision Oncology, Reverse-Phase Protein Array, Advances in Experimental Medicine and Biology2019

    • Author(s)
      Masuda M., Yamada T.
    • Total Pages
      8
    • Publisher
      Springer Nature
    • Related Report
      2018 Annual Research Report
  • [Book] 大腸がんの幹細胞増殖を抑える新規化合物発見から創薬へ2017

    • Author(s)
      増田万里
    • Total Pages
      1
    • Publisher
      日経サイエンス
    • Related Report
      2017 Annual Research Report
  • [Remarks] 国立がん研究センター研究所・連携研究室(増田グループ)

    • URL

      https://www.ncc.go.jp/jp/ri/division/genetics/project/index.html

    • Related Report
      2017 Annual Research Report
  • [Remarks] 個別医療に有用なバイオマーカーの開発

    • URL

      https://www.ncc.go.jp/jp/ri/department/clinical_proteomics/project/030/index.html

    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2023-12-25  

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