がんの発生・悪性化における微量リン脂質分子種の重要性

• Project/Area Number: 21H02680
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 佐々木 純子 東京医科歯科大学, 難治疾患研究所, 教授(キャリアアップ) (30333371)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2023: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2021: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: イノシトールリン脂質 / がん

Outline of Research at the Start

近年の解析技術の進展により、イノシトールリン脂質におけるアシル基の多様性が見出されているが、異なるアシル基を持つ各イノシトールリン脂質分子種の特異的機能は不明である。
本研究では我々が開発したリピドミクス、プロテオミクス手法や独自のツールを用いて特定のアシル基組成を有するイノシトールリン脂質の標的タンパク質を見出し、がんの発生・悪性化の新たな分子機構を明示する。

Outline of Annual Research Achievements

細胞内シグナル脂質であるイノシトールリン脂質（ＰＩＰｓ）は、グリセロール骨格に２つのアシル基とイノシトール環が結合した構造を有する。イノシトール環のリン酸化状態により７種類に分類されるＰＩＰｓは個々に特有の機能を有することが明らかになってきているが、アシル基組成の違いによるＰＩＰｓ分子種特有の機能は知られていない。
我々は、特定のアシル基組成を有するＰＩＰｓ分子種の蓄積とがんとの相関を示唆する予備的知見を得ている。そこで本研究では新たな手法の開発を通して、特定のＰＩＰｓ分子種とがんの発生・悪性化との関連を解明する。
昨年度の解析において見出したＰＩＰｓの分子種構成が大きく異なる成人細胞白血病（ＡＴＬ）由来の２つの細胞株（Ａ細胞とＢ細胞）を用いて、ＰＩＰｓの分子種構成と細胞増殖との関連を解析した。種々の脂肪酸を添加することにより、がん組織に近いあるいは正常組織に近いＰＩＰｓ分子種構成を導くことが可能であった。Ａ細胞とＢ細胞ともに、がん組織に近いＰＩＰｓ分子種構成を導く脂肪酸添加により増殖が亢進し、正常組織に近いプロファイルを導く脂肪酸添加により抑制された。すなわち、がん組織におけるＰＩＰｓ分子種が細胞増殖亢進を導いていることが示唆された。現在、昨年度の解析において見出されたがんと相関するＰＩＰｓ分子種結合タンパク質の遺伝子ノックダウン実験を行い、ＰＩＰｓの分子種と細胞増殖の関連を解析している。

Research Progress Status

令和5年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和5年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] The fatty acid elongase Elovl6 is crucial for hematopoietic stem cell engraftment and leukemia propagation (2023)
  • Author(s): Kiyoki Yusuke、Kato Takayasu、Kito Sakura、Matsuzaka Takashi、Morioka Shin、Sasaki Junko、Makishima Kenichi、Sakamoto Tatsuhiro、Nishikii Hidekazu、Obara Naoshi、Sakata-Yanagimoto Mamiko、Sasaki Takehiko、Shimano Hitoshi、Chiba Shigeru
  • Journal Title: Leukemia Volume: 37 Issue: 4 Pages: 910-913
  • DOI: 10.1038/s41375-023-01842-y
  • Peer Reviewed / Open Access
• [Journal Article] Attenuated cerebellar phenotypes in Inpp4a truncation mutants with preserved phosphatase activity. (2023)
  • Author(s): Tran DM, Yoshioka N, Bizen N, Mori-Ochiai Y, Yano M, Yanai S, Hasegawa J, Miyashita S, Hoshino M, Sasaki J, Sasaki T, Takebayashi H
  • Journal Title: Dis Model Mech Volume: 16 Issue: 7 Pages: 192-206
  • DOI: 10.1242/dmm.050169
  • Peer Reviewed / Open Access
• [Journal Article] PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate (2023)
  • Author(s): Chessa TAM, Jung P, Anwar A, Suire S, Anderson KE, Barneda D, Kielkowska A, Sadiq BA, Lai IW, Felisbino S, Turnham DJ, Pearson HB, Phillips WA, Sasaki J, Sasaki T, Oxley D, Spensberger D, Segonds-Pichon A, Wilson M, Walker S, Okkenhaug H, Cosulich S, Hawkins PT, Stephens LR
  • Journal Title: Molecular Cell Volume: 83 Issue: 16 Pages: 2991-3009.e13
  • DOI: 10.1016/j.molcel.2023.07.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model (2023)
  • Author(s): Iguchi Akihiro、Takatori Sho、Kimura Shingo、Muneto Hiroki、Wang Kai、Etani Hayato、Ito Genta、Sato Haruaki、Hori Yukiko、Sasaki Junko、Saito Takashi、Saido Takaomi C.、Ikezu Tsuneya、Takai Toshiyuki、Sasaki Takehiko、Tomita Taisuke
  • Journal Title: iScience Volume: 26 Issue: 4 Pages: 106375-106375
  • DOI: 10.1016/j.isci.2023.106375
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Minimal upstream open reading frame of Per2 mediates phase fitness of the circadian clock to day/night physiological body temperature rhythm (2023)
  • Author(s): Miyake Takahito、Inoue Yuichi、Shao Xinyan、Seta Takehito、Aoki Yuto、Nguyen Pham Khanh Tien、Shichino Yuichi、Sasaki Junko、Sasaki Takehiko、Ikawa Masahito、Yamaguchi Yoshiaki、Okamura Hitoshi、Iwasaki Shintaro、Doi Masao
  • Journal Title: Cell Reports Volume: 42 Issue: 3 Pages: 112157-112157
  • DOI: 10.1016/j.celrep.2023.112157
  • Peer Reviewed / Open Access
• [Journal Article] Tissue flow regulates planar cell polarity independently of the Frizzled core pathway (2022)
  • Author(s): Tomonori Ayukawa, Masakazu Akiyama,Yasukazu Hozumi,Kenta Ishimoto,Junko Sasaki,Haruki Senoo,Takehiko Sasaki,*Masakazu Yamazaki
  • Journal Title: Cell Reports Volume: 40 Issue: 12 Pages: 111388-111388
  • DOI: 10.1016/j.celrep.2022.111388
  • Peer Reviewed / Open Access
• [Journal Article] Plasma membrane phosphatidylinositol (4,5)-bisphosphate is critical for determination of epithelial characteristics (2022)
  • Author(s): Kaori Kanemaru, Makoto Shimozawa, Manabu Kitamata, Rikuto Furuishi, Hinako Kayano, Yui Sukawa, Yuuki Chiba, Takatsugu Fukuyama, Junya Hasegawa, Hiroki Nakanishi, Takuma Kishimoto, Kazuya Tsujita, Kazuma Tanaka, Toshiki Itoh, Junko Sasaki, Takehiko Sasaki, Kiyoko Fukami, Yoshikazu Nakamura
  • Journal Title: Nature Communications Volume: － Issue: 1 Pages: 2347-2347
  • DOI: 10.1038/s41467-022-30061-9
  • Peer Reviewed / Open Access
• [Journal Article] A mass spectrometric method for in-depth profiling of phosphoinositide regioisomers and their diseaseassociated regulation. (2022)
  • Author(s): Morioka S, Nakanishi H, Yamamoto T, Hasegawa J, Tokuda E, Hikita T, Sakihara T, Kugii Y, Oneyama C, Yamazaki M, Suzuki A, Sasaki J, Sasaki T.
  • Journal Title: Nature Communications Volume: 13(1) Issue: 1 Pages: 83-83
  • DOI: 10.1038/s41467-021-27648-z
  • Peer Reviewed / Open Access
• [Journal Article] PI4P/PS countertransport by ORP10 at ER-endosome membrane contact sites regulates endosome fission (2022)
  • Author(s): Kawasaki A, Sakai A, Nakanishi H, Hasegawa J, Taguchi T, Sasaki J, Arai H, Sasaki T, Igarashi M, Nakatsu F
  • Journal Title: J Cell Biol Volume: 221 Issue: 1 Pages: 1-19
  • DOI: 10.1083/jcb.202103141
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ホスファチジルイノシトール-3,4,5-三リン酸（PIP3）は 性分化期における精巣形成に必要である. (2023)
  • Author(s): 柳井翔吾、佐々木純子、長谷川純矢、佐々木雄彦.
  • Organizer: 第46 回分子生物学会
• [Presentation] 性維持機構におけるイノシトールリン脂質の機能の解明. (2023)
  • Author(s): 柳井翔吾、佐々木純子、佐々木雄彦.
  • Organizer: 第20 回生命 科学研究会
• [Presentation] The Role of Phospholipid Metabolism in Gonadal Maintenance. (2023)
  • Author(s): Yanai, Shogo; Sasaki Junko, Sasaki, Takehiko.
  • Organizer: The 18th international Symposium of the institute Network for Biomedical Science
  • Int'l Joint Research
• [Presentation] Phosphoinositide profiling in cancer cells and tissues. (2023)
  • Author(s): Junko Sasaki, Toshiyoshi Yamamoto, Takehiko Sasaki.
  • Organizer: The PI3K-AKT-mTOR-PTEN pathway: a new era in basic research and clinical translation
  • Int'l Joint Research
• [Presentation] Structural and Functional Dissection of Phosphoinositides. (2023)
  • Author(s): Junko Sasaki, Takehiko Sasaki.
  • Organizer: Babraham Institute seminar
  • Int'l Joint Research
• [Presentation] Structural and Functional Dissection of Phosphoinositides. (2023)
  • Author(s): Junko Sasaki, Shogo Yanai, Toshiyoshi Yamamoto, Takehiko Sasaki.
  • Organizer: University College London seminar
  • Int'l Joint Research
• [Presentation] ELOVL6 regulates engraftment of hematopoietic cells through the PI3K pathway. (2023)
  • Author(s): Yusuke Kiyoki, Takayasu Kato, Sakura Kito, Takashi Matsuzaka, Shin Morioka, Junko Sasaki, Kenichi Makishima, Tatsuhiro Sakamoto, Hidekazu Nishikii, Naoshi Obara, Mamiko Sakata-Yanagimoto, Takehiko Sasaki, Hitoshi Shimano, and Shigeru Chiba.
  • Organizer: The 28th European Hematology Association Congress
  • Int'l Joint Research
• [Presentation] Selective blockade of phosphatidylinositol-3 kinase γ suppresses the development of cutaneoussquamous cell carcinoma. (2023)
  • Author(s): Aya Toyoshima , Natsuko Noguchi , Junko Sasaki , TakehikoSasaki, Motomu Manabe , Shin-Ichi Osada.
  • Organizer: FIRST INTERNATIONAL SOCIETIES FOR INVESTIGATIVE DERMATOLOGY MEETING
  • Int'l Joint Research
• [Presentation] Phosphoinositide phosphatases in cancer (2022)
  • Author(s): Takehiko Sasaki, Junko Sasaki
  • Organizer: EMBO WORKSHOP
  • Int'l Joint Research
• [Presentation] High resolution phosphoinositide profile in pathological samples (2022)
  • Author(s): Takehiko Sasaki, Junko Sasaki
  • Organizer: FASEB science research conference
  • Int'l Joint Research
• [Presentation] Premature ovarian insufficiency in mice lacking phosphoinositide-metabolizing enzymes. (2022)
  • Author(s): Junko Sasaki, Shogo Yanai, Junjie Huang, Junya Hasegawa, Takehiko Sasaki
  • Organizer: The 17th International Symposium of the Institute Network for Biomedical Sciences & International Symposium on Tumor Biology in Kanazawa 2022
  • Int'l Joint Research
• [Presentation] Phosphoinositide dynamics in cancer (2022)
  • Author(s): Takehiko Sasaki, Junko Sasaki
  • Organizer: Symposium on World Cancer Research 2022 (SWCR)
  • Int'l Joint Research
• [Presentation] A new insight into the roles of phosphoinositides in lysosomal function. (2021)
  • Author(s): Junya Hasegawa, Lois S. Weisman, Junko Sasaki, Takehiko Sasaki.
  • Organizer: The 44th Annual Meeting of the Molecular Biology Society of Japan
  • Int'l Joint Research
• [Presentation] Biology of phosphoinositide acyl chains. (2021)
  • Author(s): チョウ イシン、佐々木 純子、佐々木 雄彦
  • Organizer: 第20回次世代を担う若手のためのファーマ・バイオフォーラム2021
• [Remarks]
  • URL: https://sites.google.com/view/byoutaiseirikagaku-university
• [Remarks] 東京医科歯科大学 難治疾患研究所 病態生理化学分野
  • URL: https://sites.google.com/view/byoutaiseirikagaku-university