Therapeutic strategies for cancer stem cells by regulating cellular differentiation based on actin dynamics

• Project/Area Number: 16K18426
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Keio University
• Principal Investigator: NOBUSUE HIROYUKI 慶應義塾大学, 医学部(信濃町), 特任助教 (90525685)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 分化制御 / アクチン細胞骨格 / 骨肉腫 / がん幹細胞 / 脂肪分化 / 癌幹細胞

Outline of Final Research Achievements

Osteosarcoma-initiating (OSi) cells are composed of two distinct types: AO cells, which have characteristics similar to mesenchymal stem cells, and AX cells, which have those similar to osteo-chondro progenitor cell and highly tumorigenic. We found that AO cells are highly resistant to chemotherapeutic agents, such as adriamycin and cisplatin. Treatment with the ROCK inhibitor fasudil alone induced remodeling of the actin cytoskeleton and inactivation of the transcriptional coactivator MKL1, resulting in the terminal adipocyte differentiation of chemoresistant stem-like AO cells. Furthermore, fasudil significantly suppressed in vitro growth and in vivo tumorigenesis of AO cells. Our findings suggest that induction of trans-differentiation by regulating actin cytoskeleton dynamics is a potential approach for chemoresistant stem-like OS cells.

Research Products

• [Journal Article] Simvastatin-Induced Apoptosis in Osteosarcoma Cells: A Key Role of RhoA-AMPK/p38 MAPK Signaling in Antitumor Activity. (2017)
  • Author(s): Kamel WA, Sugihara E, Nobusue H, Yamaguchi-Iwai S, Onishi N, Maki K, Fukuchi Y, Matsuo K, Muto A, Saya H, Shimizu T.
  • Journal Title: Molecular Cancer Therapeutics Volume: 16 Pages: 182-192
  • Peer Reviewed
• [Presentation] Therapeutic strategies for osteosarcoma stem cells by regulating adipocyte differentiation based on actin dynamics (2017)
  • Author(s): Hiroyuki Nobusue, Nobuhiro Takahashi, Nobuyuki Onishi, Takatsune Shimizu, Eiji Sugihara, Yoshinao Oki, Koichi Akashi, Koichiro Kano, Hideyuki Saya
  • Organizer: American Association for Cancer Research Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] Therapeutic strategies for osteosarcoma stem cells by regulating adipocyte differentiation based on actin dynamics (2017)
  • Author(s): Hiroyuki Nobusue, Nobuhiro Takahashi, Haruko Kunitomi, Eiji Sugihara, Takatsune Shimizu, Nobuyuki Onishi, Sayaka Yamaguchi-Iwai, Hideyuki Saya
  • Organizer: ASCB/EMBO 2017 meeting
  • Int'l Joint Research
• [Presentation] Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation (2016)
  • Author(s): 信末博行、佐谷秀行
  • Organizer: 日本遺伝学会 第88回大会
  • Place of Presentation: 日本大学国際関係学部 三島駅北口校舎（静岡県・三島市）
  • Year and Date: 2016-09-07
  • Invited
• [Presentation] Therapeutic strategies for osteosarcoma stem cells by regulating adipocyte differentiation based on actin dynamics (2016)
  • Author(s): Hiroyuki Nobusue, Nobuhiro Takahashi, Nobuyuki Onishi, Takatsune Shimizu, Eiji Sugihara, Yoshinao Oki, Tatsuyuki Chiyoda, Koichi Akashi, Koichiro Kano, Hideyuki Saya
  • Organizer: 第14回幹細胞シンポジウム
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県・淡路市）
  • Year and Date: 2016-05-20
  • Invited