Development of therapy that targets ovarian clear cell carcinoma stem cells

• Project/Area Number: 24501313
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kyoto Prefectural University of Medicine (2013-2014); The University of Tokyo (2012)
• Principal Investigator: NASU Ryo 京都府立医科大学, 医学(系)研究科(研究院), 助教 (30466859)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 癌 / 癌幹細胞 / 卵巣明細胞癌 / CD133 / Wntシグナル / LGR5 / デスモソーム

Outline of Final Research Achievements

Clear cell carcinoma of the ovary (CCC) has the worst prognosis among epithelial ovarian cancers because of its chemoresistance. In this study, we tried to develop a new therapy that targets CCC stem cells. We analyzed the gene expression profile of CCC stem cells established by our group and found the high expression of the stem cell marker LGR5. Moreover, we analyzed the molecular mechanisms of the activation of Wnt signaling by the R-spondin-LGR5 axis and found that R-spondin/Wnt stimuli activate Wnt signaling via promoting novel phosphorylation of Axin1. Thus, both antibodies that target the extracellular domain of LGR5 and small molecules that inhibit Axin1 phosphorylation hold promise as novel anti-tumor reagents.

Research Products

• [Journal Article] Thr160 of Axin1 is critical for the formation and function of the β-catenin destruction complex. (2015)
  • Author(s): Koyama-Nasu R, Hayashi T, Nasu-Nishimura Y, Akiyama T, Yamanaka R
  • Journal Title: Biochem Biophys Res Commun. Volume: 459 Issue: 3 Pages: 411-415
  • DOI: 10.1016/j.bbrc.2015.02.118
  • Peer Reviewed
• [Journal Article] SOX9-mediated upregulation of LGR5 is important for glioblastoma tumorigenicity. (2015)
  • Author(s): Hiraoka K, Hayashi T, Kaneko R, Nasu-Nishimura Y, Koyama-Nasu R, Kawasaki Y, Akiyama T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 460 Issue: 2 Pages: 4097-4109
  • DOI: 10.1016/j.bbrc.2015.03.012
  • Peer Reviewed
• [Journal Article] 5-Hydroxymethylcytosine Plays a Critical Role in Glioblastomagenesis by Recruiting the CHTOP-Methylosome Complex (2014)
  • Author(s): Hiroki Takai, Tetsu Akiyama et al.
  • Journal Title: Cell Reports Volume: 9 Issue: 1 Pages: 48-60
  • DOI: 10.1016/j.celrep.2014.08.071
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PCDH10 is required for the tumorigenicity of glioblastoma cells (2014)
  • Author(s): Kanae Echizen, Mitsutoshi Nakada , Tomoatsu Hayashi, Hemragul Sabit, Takuya Furuta, Miyuki Nakai, Ryo Koyama-Nasu, Yukiko Nishimura, Kenzui Taniue, Yasuyuki Morishita, Shinji Hirano, Kenta Terai, Tomoki Todo, Yasushi Ino, Akitake Mukasa, Shunsaku Takayanagi, Ryohei Ohtani, Nobuhito Saito, Tetsu Akiyama
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 444 Issue: 1 Pages: 13-18
  • DOI: 10.1016/j.bbrc.2013.12.138
  • Peer Reviewed / Open Access
• [Journal Article] The pleiotrophin-ALK axis is required for tumorigenicity of glioblastoma stem cells (2013)
  • Author(s): R Koyama-Nasu, R Haruta, Y Nasu-Nishimura, K Taniue, Y Katou, K Shirahige, T Todo, Y Ino, A Mukasa, N Saito, M Matsui, R Takahashi, A Hoshino-Okubo, H Sugano, E Manabe, K Funato and T Akiyam
  • Journal Title: Oncogene Volume: 33 Issue: 17 Pages: 2236-2244
  • DOI: 10.1038/onc.2013.168
  • Peer Reviewed / Open Access
• [Journal Article] The cancer stem cell marker CD133 interacts with plakoglobin and controls desmoglein-2 protein levels. (2013)
  • Author(s): Koyama-Nasu R, Takahashi R, Yanagida S, Nasu-Nishimura Y, Oyama M, Kozuka-Hata H, Haruta R, Manabe E, Hoshino-Okubo A, Omi H, Yanaihara N, Okamoto A, Tanaka T, and Akiyama T.
  • Journal Title: PLoS One Volume: 8 Issue: 1 Pages: e53710-e53710
  • DOI: 10.1371/journal.pone.0053710
  • Peer Reviewed
• [Journal Article] The critical role of cyclin D2 in cell cycle progression and tumorigenicity of glioblastoma stem cells (2013)
  • Author(s): R Koyama-Nasu, Y Nasu-Nishimura, T Todo, Y Ino, N Saito, H Aburatani, K Funato, K Echizen, H Sugano, R Haruta, M Matsui, R Takahashi, E Manabe, T Oda and T Akiyama
  • Journal Title: Oncogene Volume: 32 Issue: 33 Pages: 3840-3845
  • DOI: 10.1038/onc.2012.399
  • Peer Reviewed
• [Journal Article] Global proteome analysis of glioblastoma stem cells by high-resolution mass spectrometry (2012)
  • Author(s): Kozuka-Hata H, Nasu-Nishimura Y, Koyama-Nasu R, Ao-Kondo H, Tsumoto K, Akiyama T & Oyama M
  • Journal Title: Current Topics in Peptide & Protein Research Volume: 13 Pages: 1-47
• [Journal Article] Phosphoproteome of human glioblastoma initiating cells reveals novel signaling regulators encoded by the transcriptome. (2012)
  • Author(s): Kozuka-Hata H, Nasu-Nishimura Y, Koyama-Nasu R, Ao-Kondo H, Tsumoto K, Akiyama T, and Oyama M.
  • Journal Title: PLoS One Volume: 7 Issue: 8 Pages: e43398-e43398
  • DOI: 10.1371/journal.pone.0043398
  • Peer Reviewed
• [Presentation] The SOX2-pleiotrophin-ALK axis is required for tumorigenicity of glioblastoma stem cells (2012)
  • Author(s): 那須 亮、春田 諒、西村 教子、谷上 賢端、加藤 由起、白髭 克彦、藤堂 具紀、稲生 靖、武笠 晃丈、齊藤 延人、松井 真弓、髙橋 理那、大久保 明美、菅野 陽元、真鍋 瑛美、船戸 洸佑、秋山 徹
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡(福岡)
• [Presentation] The cancer stem cell marker CD133 is required for desmosome formation (2012)
  • Author(s): 那須 亮、髙橋 理那、柳田 聡、西村 教子、尾山 大明、秦 裕子、春田 諒、眞鍋 瑛美、大久保 明美、尾見 裕子、矢内原 臨、岡本 愛光、田中 忠男、秋山 徹
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ホテルロイトン札幌(北海道)