Development of novel treatment strategies targeting the R-spondin-LGR-APC axis in glioblastoma stem cells

• Project/Area Number: 15K06838
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Chiba University (2016-2017); Tokai University (2015)
• Principal Investigator: NASU Ryo 千葉大学, 大学院医学研究院, 特任助教 (30466859)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: がん / がん幹細胞 / 膠芽腫 / Wntシグナル / がん免疫 / 癌 / 癌幹細胞 / LGR5 / APC / Axin1 / 腫瘍免疫

Outline of Final Research Achievements

Glioblastoma is the most common and aggressive malignant brain tumor in adults. In this study, we tried to develop a new therapy that targets the interaction of glioblastoma stem cells with their specific microenvironments. We found a crucial role of the R-spondin-LGR5-APC axis in the control of Wnt signaling in glioblastoma stem cells. Moreover, R-spondin/Wnt stimuli activate Wnt signaling via promoting the phosphorylation of Axin1 at T160. Thus, small molecules that inhibit Axin1 T160 phosphorylation hold promise as novel anti-tumor reagents.

Research Products

• [Journal Article] Anti-tumor immunity via the superoxide-eosinophil axis induced by a lipophilic component of Mycobacterium lipomannan (2017)
  • Author(s): Ito Toshihiro、Hirahara Kiyoshi、Onodera Atsushi、Koyama-Nasu Ryo、Yano Ikuya、Nakayama Toshinori
  • Journal Title: Int. Immunol Volume: 29 Issue: 9 Pages: 411-421
  • DOI: 10.1093/intimm/dxx051
  • Peer Reviewed / Open Access
• [Journal Article] Imbalanced expression of polycistronic miRNA in acute myeloid leukemia. (2017)
  • Author(s): Kotaki R, Higuchi H, Ogiya D, Katahira Y, Kurosaki N, Yukihira N, Ogata J, Yamamoto H, Mohamad Alba S, Azhim A, Kitajima T, Inoue S, Morishita K, Ono K, Koyama-Nasu R, Kotani A.
  • Journal Title: Int J Hematol. Volume: 106 Issue: 6 Pages: 811-819
  • DOI: 10.1007/s12185-017-2314-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] miRNAs in Normal and Malignant Hematopoiesis (2017)
  • Author(s): Ryutaro Kotaki, Ryo Koyama-Nasu, Natsuko Yamakawa, Ai Kotani
  • Journal Title: International Journal of Molecular Sciences Volume: 18(7) Issue: 7 Pages: 1495-1495
  • DOI: 10.3390/ijms18071495
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrative Network Analysis Combined with Quantitative Phosphoproteomics Reveals TGFBR2 as a Novel Regulator of Glioblastoma Stem Cell Properties (2016)
  • Author(s): Narushima Y, Kozuka-Hata H, Koyama-Nasu R, Tsumoto K, Inoue J, Akiyama T & Oyama M.
  • Journal Title: Molecular and Cellular Proteomics Volume: 15 Issue: 3 Pages: 1017-1031
  • DOI: 10.1074/mcp.m115.049999
  • Peer Reviewed / Open Access
• [Presentation] 高深度定量リン酸化プロテオミクスと大規模インタラクトーム情報を基盤とする膠芽腫幹細胞情報伝達系の統合ネットワーク解析 (2016)
  • Author(s): 秦裕子, 成島悠太, 廣木朋子, 那須亮, 津本浩平, 井上純一郎, 秋山徹, 尾山大明
  • Organizer: 第39回 日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市)
  • Year and Date: 2016-11-30
• [Presentation] Functional and comprehensive investigation of microRNA targeting Notch receptors (2016)
  • Author(s): 那須亮, 奥山一生, 扇屋大輔, 穂積勝人, 村田暁彦, 安藤潔, 幸谷愛
  • Organizer: 第14回 幹細胞シンポジウム
  • Place of Presentation: 兵庫県立淡路夢舞台国際会議場 (兵庫県淡路市))
  • Year and Date: 2016-05-20
• [Presentation] Identification of Notch-targeting miRNA that regulates B cell development and has therapeutic potential in T-ALL. (2016)
  • Author(s): 那須亮, 奥山一生, 扇屋大輔, 穂積勝人, 村田暁彦, 安藤潔, 幸谷愛
  • Organizer: 第20回造血器腫瘍研究会
  • Place of Presentation: かずさアーク (千葉)
  • Year and Date: 2016-02-12
• [Presentation] mTOR阻害剤を用いた膠芽腫幹細胞プロテオーム及びリン酸化プロテオームに関する統合摂動実験 (2015)
  • Author(s): 秦裕子, 廣木朋子, 那須亮, 津本浩平, 井上純一郎, 秋山徹, 尾山大明
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド (兵庫)
  • Year and Date: 2015-12-01
• [Presentation] 高精度定量リン酸化プロテオミクスに基づく統合ネットワーク解析による膠芽腫幹細胞分化制御因子の同定 (2015)
  • Author(s): 成島悠太, 秦裕子, 那須亮, 津本浩平, 井上純一郎, 秋山徹, 尾山大明
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド (兵庫)
  • Year and Date: 2015-12-01
• [Presentation] Identification of Notch-targeting miRNA that regulates B cell development and has therapeutic potential in T-ALL. (2015)
  • Author(s): 那須亮, 奥山一生, 扇屋大輔, 穂積勝人, 村田暁彦, 安藤潔, 幸谷愛
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場 (愛知)
  • Year and Date: 2015-10-08
• [Remarks] 千葉大学大学院医学研究院免疫発生学
  • URL: http://www.m.chiba-u.ac.jp/class/meneki/
• [Remarks] 千葉大学大学院医学研究院免疫発生学
  • URL: http://www.m.chiba-u.ac.jp/class/meneki/index.html