Exosomal secretion of hypoxia-adapted multiple myeloma cells

• Project/Area Number: 20K17388
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: Toda Yuki 京都薬科大学, 薬学部, 助教 (40779724)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 低酸素 / Exosomes / HK2 / ミトコンドリア / 分泌制御機構 / Exosome分泌 / 分泌制御シグナル / HK2発現制御 / 細胞生存 / 細胞内シグナル伝達 / exosome分泌 / tet-on / ALIX / ミトコンドリア分画

Outline of Research at the Start

多発性骨髄腫（MM）において、既存治療に抵抗性を示すがん幹細胞（MM幹細胞）は骨髄の低酸素環境に存在している。MM幹細胞は多様な生体分子（miRNAなど）を含む小胞（exosomes）を過剰に分泌している。本研究ではexosome分泌に着目し、低酸素環境に潜むMM幹細胞の生存との関わりを明らかにする。Exosomeの分泌がどのように制御され、MM幹細胞の生存に関わるのか解明されれば、それを糸口にした新たな治療法を提案できる。MM幹細胞の弱点を突いた治療は、MMを治癒の望める疾患へと変える可能性を有している。以上より本研究は、MM患者に大きな福音をもたらしうる、社会的意義の高い基礎研究である。

Outline of Final Research Achievements

Ineffectiveness of traditional therapies against cancer stem cells (CSCs) is reportedly associated with the poor outcome for multiple myeloma (MM) patients. Myeloma stem cells reside in hypoxic bone marrow niche where maintains their stem cell property. We previously established MM cells experienced long-term exposure of hypoxia and characterized their enhanced stem cell characteristics. The hypoxia-adapted (HA) cells require exosomal secretion for their survival in hypoxic condition. In this study, we identified Akt/AS160 signal as a regulatory signal for the exosome secretion and demonstrated mitochondrial localization of hexokinase 2 with anti-apoptotic function which was possibly involved in survival of HA-MM cells. The study provides insights in design novel therapy for prevention of recurrence resulting from myeloma stem cells.

Academic Significance and Societal Importance of the Research Achievements

多発性骨髄腫（MM）の再発に関与する幹細胞性の高い集団（骨髄腫幹細胞）は、骨髄低酸素環境に存在すると言われている。代表者は、上記骨髄腫幹細胞を低酸素環境での長期培養によって再現し、その生存に細胞外小胞（exosomes）の分泌が関与することを見出した。さらに本課題ではその分泌制御に関わるシグナルおよび生存メカニズムの一部を明らかにした。本知見を基盤とする、骨髄腫幹細胞を標的とした再発を防ぐ治療法の開発が期待される。

Research Products

• [Journal Article] Hypoxia-adapted Multiple Myeloma Stem Cells Resist γδ-T-Cell-mediated Killing by Modulating the Mevalonate Pathway (2023)
  • Author(s): Yusuke Sano、Naoko Kuwabara、Saori Nakagawa、Yuki Toda、Shigekuni Hosogi、Shinji Sato、Eishi Ashihara
  • Journal Title: Anticancer Research Volume: 43 Issue: 2 Pages: 547-555
  • DOI: 10.21873/anticanres.16191
  • Peer Reviewed
• [Journal Article] 7,8-Dihydroxy-3-(4′-hydroxyphenyl)coumarin inhibits invasion and migration of osteosarcoma cells (2023)
  • Author(s): Sugiyama Yuki、Nakamura Seikou、Tokuda Yuichi、Nakano Masakazu、Hattori Yasunao、Nishiguchi Hiroki、Toda Yuki、Hosogi Shigekuni、Yamashita Masayuki、Tashiro Kei、Ashihara Eishi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 638 Pages: 200-209
  • DOI: 10.1016/j.bbrc.2022.11.056
  • Peer Reviewed
• [Journal Article] CN470 is a BET/CBP/p300 multi-bromodomain inhibitor and has an anti-tumor activity against MLL-rearranged acute lymphoblastic leukemia (2022)
  • Author(s): Imayoshi Natsuki、Yoshioka Makoto、Tanaka Kuniaki、Yang Shyh-Ming、Akahane Koshi、Toda Yuki、Hosogi Shigekuni、Inukai Takeshi、Okada Seiji、Maloney David J.、Nakahata Tatsutoshi、Takita Junko、Kato Itaru、Ashihara Eishi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 590 Pages: 49-54
  • DOI: 10.1016/j.bbrc.2021.12.078
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Successful Incorporation of Exosome-Capturing Antibody-siRNA Complexes into Multiple Myeloma Cells and Suppression of Targeted mRNA Transcripts (2022)
  • Author(s): Soma Emi、Yamayoshi Asako、Toda Yuki、Mishima Yuji、Hosogi Shigekuni、Ashihara Eishi
  • Journal Title: Cancers Volume: 14 Issue: 3 Pages: 566-566
  • DOI: 10.3390/cancers14030566
  • Peer Reviewed / Open Access
• [Journal Article] The CDK4/6-UCHL5-BRD4 axis confers resistance to BET inhibitors in MLL-rearranged leukemia cells by suppressing BRD4 protein degradation (2022)
  • Author(s): Amari Keigo、Sasagawa Satoru、Imayoshi Natsuki、Toda Yuki、Hosogi Shigekuni、Imamura Toshihiko、Ashihara Eishi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 588 Pages: 147-153
  • DOI: 10.1016/j.bbrc.2021.12.063
  • Peer Reviewed
• [Journal Article] Expression level of BTN3A1 on the surface of CD14+ monocytes is a potential predictor of γδ T cell expansion efficiency (2022)
  • Author(s): Tomogane Mako、Omura Maho、Sano Yusuke、Shimizu Daiki、Toda Yuki、Hosogi Shigekuni、Kimura Shinya、Ashihara Eishi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 588 Pages: 47-54
  • DOI: 10.1016/j.bbrc.2021.12.060
  • Peer Reviewed
• [Journal Article] Human Vγ9Vδ2?T cells exert anti-tumor activity independently of PD-L1 expression in tumor cells (2021)
  • Author(s): Tomogane Mako、Sano Yusuke、Shimizu Daiki、Shimizu Teruki、Miyashita Masatsugu、Toda Yuki、Hosogi Shigekuni、Tanaka Yoshimasa、Kimura Shinya、Ashihara Eishi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 573 Pages: 132-139
  • DOI: 10.1016/j.bbrc.2021.08.005
  • Peer Reviewed / Open Access
• [Journal Article] A novel dipeptide type inhibitor of the Wnt/b-catenin pathway suppresses proliferation of acute myelogenous leukemia cells. (2021)
  • Author(s): Ryosuke Wakabayashi, Yasunao Hattori, Shigekuni Hosogi, Yuki Toda, Kazuyuki Takata, Eishi Ashihara.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 535 Pages: 73-79
  • DOI: 10.1016/j.bbrc.2020.12.027
  • Peer Reviewed
• [Journal Article] Factors Associated with Dose Modification of Lenalidomide Plus Dexamethasone Therapy in Multiple Myeloma (2020)
  • Author(s): Yoko Kado, Masayuki Tsujimoto, Shin-ichi Fuchida, Akira Okano, Mayumi Hatsuse, Satoshi Murakami, Hikofumi Sugii, Kumi Ueda, Yuki Toda, Tetsuya Minegaki, Kohshi Nishiguchi, Yuichi Muraki, Chihiro Shimazaki, Eishi Ashihara.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 8 Pages: 1253-1258
  • DOI: 10.1248/bpb.b20-00337
  • NAID: 130007883792
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-08-01
  • Peer Reviewed
• [Journal Article] Mouse Bone Marrow-derived Microglia-like Cells Secrete Transforming Growth Factor-β1 and Promote Microglial Aβ Phagocytosis and Reduction of Brain Aβ (2020)
  • Author(s): Kuroda E, Nishimura K, Kawanishi S, Sueyoshi M, Ueno F, Toji Y, Abo N, Konishi T, Harada K, Satake S, Shima C, Toda Y, Kitamura Y, Shimohama S, Ashihara E, Takata K.
  • Journal Title: Neuroscience Volume: 438 Pages: 217-228
  • DOI: 10.1016/j.neuroscience.2020.05.004
  • Peer Reviewed / Open Access
• [Presentation] 転移予定臓器における組織酸性化の転移巣形成への寄与 (2023)
  • Author(s): 小西和也, 松井透磨, 戸田侑紀, 細木誠之, 芦原英司
  • Organizer: 日本薬学会 第143年会
• [Presentation] pH-low insertion peptide detects lactic acidosis contributing metastatic niche formation in lungs (2022)
  • Author(s): Toma Matsui, Yuki Toda, Anna Mosnikova, Oleg A. Andreev, Shigekuni Hosogi, Yana K. Reshetnyak, Eishi Ashihara
  • Organizer: American Association for Cancer Research Special Conference: CANCER METASTASIS
  • Int'l Joint Research
• [Presentation] pH-low insertion peptide accumulated in lung metastatic niche with lactic acidosis (2022)
  • Author(s): Toma Matsui, Yuki Toda, Shigekuni Hosogi, Eishi Ashihara
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] pH-low insertion peptideで捉える転移予定臓器における組織pHの変化 (2022)
  • Author(s): 戸田侑紀, 松井透磨, 細木誠之, 芦原英司
  • Organizer: 第26回日本がん分子標的治療学会学術集会
• [Presentation] pH-low insertion peptideを用いた転移予定臓器における組織酸性化の検出 (2022)
  • Author(s): 松井透磨、戸田侑紀、中井亮太、横川碧、板垣里奈、細木誠之、芦原英司
  • Organizer: 日本薬学会 第142年会
• [Presentation] Detection of acidic environment in metastatic niche by pH-low insertion peptide (2022)
  • Author(s): Toma Matsui、Yuki Toda、Eiko Sawada、Aoi Yokogawa、Ryota Nakai、Rina Itagaki、Anna Mosnikova、Oleg A. Andreev、Shigekuni Hosogi、Yana K. Reshetnyak、Eishi Ashihara
  • Organizer: The 5th International Cancer Research Symposium - a Training for Oncology Professionals
  • Int'l Joint Research
• [Presentation] UCHL5 overexpression confers resistance to BETi in MLL-r leukemia cells by suppressing degradation of BRD4 protein (2021)
  • Author(s): Keigo Amari、Yuki Toda、Shigekuni Hosogi、Toshihiko Imamura、Eishi Ashihara
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] A novel coumarin-based compound inhibits invasion and migration of osteosarcoma cells (2021)
  • Author(s): Yuki Sugiyama、Seikou Nakamura、Kimika Yamaguchi、Yasunao Hattori、Yuki Toda、Shigekuni Hosogi、Eishi Ashihara
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] A novel dipeptide type Wnt/β-catenin pathway inhibitor suppresses proliferation of acute myelogenous leukemia cells (2021)
  • Author(s): Yuki Hadate、Ryosuke Wakabayashi、Yasunao Hattori、Shigekuni Hosogi、Yuki Toda、Kazuyuki Takata、Eishi Ashihara
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Acidic microenvironment increased the anti-tumor effect of γδT cell on A549 lung cancer cells (2021)
  • Author(s): Shura Yarimizu、Shigekuni Hosogi、Mina Suzuki、Nobuhisa Tohdo、Daiki Shimizu、Yusuke Sano、Natsuki Imayoshi、Keigo Amari、Makou Tomogane、Yuki Toda、Eishi Ashihara
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Application of BET/CBP/p300 multi-bromodomain inhibitors as a novel therapeutic strategy for MLL-rearranged acute lymphoblastic leukemia (2020)
  • Author(s): Natsuki Imayoshi, Makoto Yoshioka, Shyh-Ming Yang, Koshi Akahane, Yuki Toda, Shigekuni Hosogi, Takeshi Inukai, Seiji Okada, David J. Maloney, Jeffrey W. Strovel, Eishi Ashihara.
  • Organizer: American Association for Cancer Research Annual Meeting 2020
  • Int'l Joint Research
• [Presentation] Cdk4/6 inhibitor Abemaciclib overcomes resistance to BET inhibitor in leukemic cells with MLL-AF5q31 fusion gene (2020)
  • Author(s): Keigo Amari, Yuki Toda, Shigekuni Hosogi, Toshihiko Imamura, Eishi Ashihara.
  • Organizer: American Association for Cancer Research Annual Meeting 2020
  • Int'l Joint Research
• [Presentation] 急性骨髄性白血病に対する新規ペプチド型Wnt/β-catenin阻害剤の効果 (2020)
  • Author(s): 若林亮介, 服部恭尚, 戸田侑紀, 細木誠之, 芦原英司
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] γδT細胞の体外増幅培養における予測可能なバイオマーカーの探索 (2020)
  • Author(s): 友金眞光, 宮下雅亜, 佐野友亮, 清水大器, 戸田侑紀, 細木誠之, 芦原英司
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 低酸素環境に適応した多発性骨髄腫に対するγδT細胞の抗腫瘍効果 (2020)
  • Author(s): 佐野友亮, 友金眞光, 清水大器, 宮下雅亜, 戸田侑紀, 細木誠之, 芦原英司
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 骨髄系細胞が動員された前転移ニッチにおける乳酸アシドーシス (2020)
  • Author(s): 松井透磨, 戸田侑紀, 細木誠之, 芦原英司
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Novel BET/CBP/p300 multi-bromodomain inhibitors as a strategy for MLL-rearranged ALL (2020)
  • Author(s): Natsuki Imayoshi, Makoto Yoshioka, Kuniaki Tanaka, Shyh-Ming Yang, Koshi Akahane, Yuki Toda, Shigekuni Hosogi, Takeshi Inukai, Seiji Okada, David J. Maloney, Itaru Kato, Eishi Ashihara.
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Cdk4/6i Abemaciclib overcomes resistance to BETi in leukemic cells with MLL-AF5q31 fusion gene (2020)
  • Author(s): Keigo Amari, Yuki Toda, Shigekuni Hosogi, Toshihiko Imamura, Eishi Ashihara.
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] MLL-AF5q31 cells acquire BET inhibitor resistance by Brd4-regulated molecules upregulation (2020)
  • Author(s): Keigo Amari, Yuki Toda, Shigekuni Hosogi, Toshihiko Imamura, Eishi Ashihara.
  • Organizer: Global Academic Programs 2020
  • Int'l Joint Research
• [Remarks] 京都薬科大学病態生理学分野
  • URL: https://labo.kyoto-phu.ac.jp/seiri/seiri-j.html
• [Remarks] 京都薬科大学病態生理学分野ホームページ
  • URL: https://labo.kyoto-phu.ac.jp/seiri/pg402.html