Elucidation of molecular and cellular basis for niche development toward cancer stem cell regulation

• Project/Area Number: 17K07156
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Tabu Kouichi 東京医科歯科大学, 難治疾患研究所, 助教 (10466469)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: がん幹細胞 / 微小環境 / ニッチ / 治療抵抗性 / 再発 / ポリマー / 高分子 / 亜集団 / ケミカルプローブ / 人工ニッチ / がん / 癌幹細胞 / ニッチ形成 / 死細胞 / ネクローシス / マクロファージ / 貪食 / 鉄欠乏 / 単球 / CCL2 / レポーター細胞 / 不均一性 / 鉄 / ストレス応答

Outline of Final Research Achievements

This study was carried out with the aim of developing the therapies targeting cancer stem cells (CSCs) and their microenvironments (niche). We have revealed that a subpopulation of CSCs has the comprehensive role for constructing niche and that such niche-constructing CSCs (ncCSCs) are dramatically enriched after the treatment of anti-glioma drug Temozolomide. We also identified some biomimetic polymer compounds that promote or inhibit the expansion of ncCSCs. Our findings could help develop new therapeutics for CSCs/niche intervention, potentially leading to cancer eradication.

Academic Significance and Societal Importance of the Research Achievements

がん微小環境（ニッチ）を構成する分子・細胞要素は極めて多岐に渡ることから、それらの包括的な理解と制御は未だ達成されていない。本研究におけるニッチ構築がん幹細胞の同定は、がん微小環境の全容解明を飛躍的に促す足掛かりとなる成果であり、高い学術的意義を有する。また、従来の低分子抗がん剤に耐性の高いがん幹細胞に対し機能性のポリマーを同定できたことは新たながん根絶技術の開発を期待できる成果であり、大きな社会的意義を有する。

Research Products

• [Int'l Joint Research] The University of Edinburgh(英国)
• [Int'l Joint Research] University of Edinburgh(英国)
• [Int'l Joint Research] University of Edinburgh(英国)
• [Journal Article] Glioma stem cell (GSC)-derived autoschizis-like products confer GSC niche properties involving M1-like tumor-associated macrophages (2020)
  • Author(s): Tabu K, Liu W, Kosaku A, Terashima K, Murota Y, Aimaitijiang A, Nobuhisa I, Hide T and Taga T
  • Journal Title: Stem Cells Volume: - Issue: 8 Pages: 921-935
  • DOI: 10.1002/stem.3193
  • Peer Reviewed
• [Journal Article] 合成ポリマーを用いたがん幹細胞ニッチの解析 (2020)
  • Author(s): 椨康一、田賀哲也
  • Journal Title: 週刊医学のあゆみ Volume: 273 Pages: 474-479
• [Presentation] Synthetic polymer-based stratification of soft tissue sarcomas with different gene alterations and cells of origin (2020)
  • Author(s): Tabu K, Zhang S, Kosaku A, Venkateswaran S, Kohsaka S, Bradley M, Taga T
  • Organizer: 11th World Biomaterials Congress (WBC2020)
  • Int'l Joint Research
• [Presentation] Autoschizis-like spontaneous necrosis mediates a self-expanding strategy of glioma stem cells by modulating tumor-associated macrophages (2019)
  • Author(s): 椨康一, Liu Wenyu, 秀拓一郎, 田賀哲也
  • Organizer: 第17回幹細胞シンポジウム
• [Presentation] Enhanced erythropoiesis in bone marrow of C6 glioma-bearing mice (2019)
  • Author(s): Aimaitijiang Alapati, 椨康一, Wang Wenqian, 信久幾夫, 田賀哲也
  • Organizer: 第17回幹細胞シンポジウム
• [Presentation] Visualization and validation of monocyte-recruiting cells as a potential target of glioma stem cells (2019)
  • Author(s): 椨康一, 田賀哲也
  • Organizer: 第78回日本癌学会学術集会
• [Presentation] Glioma stem cells modulate erythropoiesis in mouse bone marrow (2019)
  • Author(s): Aimaitijiang Alapati, 椨康一, 田賀哲也
  • Organizer: 第78回日本癌学会学術集会
• [Presentation] A self-expanding strategy of glioma stem cells via promoting the development of M1-like tumor-associated macrophages (2019)
  • Author(s): 椨康一, Liu Wenyu, 田賀哲也
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Development of Treatment Strategies Targeting Cancer Stem Cells (2019)
  • Author(s): Taga T and Tabu K
  • Organizer: The 3rd Meeting of International Society of Precision Cancer Medicine Annual Meeting 2019
  • Int'l Joint Research / Invited
• [Presentation] Identification of a subpopulation of glioma cells with a potential for tumor niche development involving myeloid cells (2018)
  • Author(s): Tabu K and Taga T
  • Organizer: The 16th Stem Cell Research Symposium
• [Presentation] A monocyte-recruiting phenotype defines functional heterogeneity of glioma cells with stemness and chemoresistance (2018)
  • Author(s): Tabu K and Taga T
  • Organizer: The 77th Annual Meeting of the Japanese Cancer Association
• [Presentation] 神経膠腫癌幹細胞の利己的生存戦略による癌の進展 (2017)
  • Author(s): 田賀哲也、椨康一
  • Organizer: 第38回日本 炎症・再生医学会
  • Invited
• [Presentation] Self-expanding strategies of glioma stem cells that involves macrophages to adapt to iron-deprivation stress (2017)
  • Author(s): Tabu K, Wang W, Murota Y and Taga T
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Presentation] Establishment of glioma mouse model by transducing oncogenic H-RasV12 gene into the p53 deficient astrocytes (2017)
  • Author(s): Murota Y, Wenqing GY, Tabu K, and Taga T
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Presentation] 宿主単球・マクロファージの誘導によるグリオーマ幹細胞の鉄欠乏ストレスへの適応：ニッチ自己構築機構の解明 (2017)
  • Author(s): 椨 康一、巽 瑠璃子、田賀 哲也
  • Organizer: Consortium of Biological Sciences 2017
• [Presentation] グリオーマ幹細胞による宿主マクロファージ制御におけるオートスキジス様細胞死の役割 (2017)
  • Author(s): 松永 浩明、椨 康一、田賀 哲也
  • Organizer: Consortium of Biological Sciences 2017
• [Presentation] 膵臓癌幹細胞ニッチを擬態する合成ポリマーのスクリーニング (2017)
  • Author(s): 室田 吉貴、Sara Schmidt、椨 康一、伊藤 浩光、田中 真二、Mark Bradley、田賀 哲也
  • Organizer: Consortium of Biological Sciences 2017
• [Presentation] Screening for human pancreatic cancer stem cell niche mimicry by using synthetic polymer microarrays (2017)
  • Author(s): Murota Y, Schmidt S, Tabu K, Ito H, Tanaka S, Bradley M and Taga T
  • Organizer: The 15th Stem Cell Research Symposium
• [Book] 次世代がん治療 (2017)
  • Author(s): 椨康一、田賀哲也
  • Total Pages: 386
  • Publisher: 株式会社エヌ・ティー・エス
• [Remarks] 東京医科歯科大学難治疾患研究所幹細胞制御分野ホームページ
  • URL: http://www.tmd.ac.jp/mri/scr/index.html