Mechanisms of pancreatic carcinogenesis by metabolic changes in human pancreatic epithelial cells with mutated kRas gene

• Project/Area Number: 21K15368
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Suzuki Tatsunori 東京大学, 医学部附属病院, 助教 (40882890)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 膵がん / 膵癌 / 代謝リプログラム

Outline of Research at the Start

膵癌の多段階発癌過程では初期のKRAS遺伝子変異がほぼ必発であるが、その変異が起きた後、どのような生物学的変化が生じて、どのように他の遺伝子の変異が蓄積されて癌化するのか、その後の明確な分子機構は分かっていない。本研究では、KRAS変異が導入された膵管上皮細胞で惹起されるグルタミン・アスパラギン酸の枯渇がプリン・ピリミジンプールのインバランスを惹起し、その他のドライバー遺伝子の変異を続発的に誘発するのではないか、すなわち「遺伝子変異が惹起する代謝リプログラミングによる細胞癌化機構」というコンセプトを検証し、膵癌化機構の一端を解明する。

Outline of Final Research Achievements

Mutations in the KRAS gene almost always occur in pancreatic cancer, but the clear molecular mechanism by which biological changes occur after this mutation occurs and mutations in other genes accumulate and turn into cancer is not known. It wasn't. In this study, we identified that KRAS gene mutations cause changes in intracellular amino acid metabolism, mainly asparagine, and that autophagy as a compensatory mechanism is essential for the survival of pancreatic ductal epithelial cells with KRAS gene mutations. We discovered the possibility of preventing cancer through intervention. These results can be said to reveal the mechanism by which human normal pancreatic ductal epithelial cells into which KRAS gene mutations are introduced accumulate mutations after KRAS gene mutations during the early stages of pancreatic carcinogenesis.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、膵発癌の初期過程に関わる因子、遺伝子変異の蓄積機構を解明することができた。癌細胞が引き起こす代謝リプログラミングに関しては多くの知見が得られつつあるが、本研究はKRAS変異を導入したヒトの正常膵管上皮細胞を解析することで膵発癌の初期過程を解明する研究を進めることができた。特に「遺伝子変異がもたらす代謝変化が更なる遺伝子変異をもたらし発癌過程を促進する可能性」については十分に検討されておらず大きなブレークスルーをもたらす可能性がある。本研究で、KRAS遺伝子変異以降の現象に対する介入による発癌予防、代謝変化を利用した膵癌の早期診断法の確立など新規開拓・創生につながる可能性がある。

Research Products

• [Journal Article] Intraductal Papillary Mucinous Neoplasm Surveillance Leads to Early Diagnosis and Better Outcomes of Concomitant Cancer (2024)
  • Author(s): Oyama Hiroki、Hamada Tsuyoshi、Nakai Yousuke、Tanaka Mariko、Takagi Kaoru、Fukuda Rintaro、Hakuta Ryunosuke、Ishigaki Kazunaga、Kanai Sachiko、et al.
  • Journal Title: Annals of Surgery Volume: -
  • DOI: 10.1097/sla.0000000000006268
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Satellite double-stranded RNA induces mesenchymal transition in pancreatic cancer by regulating alternative splicing (2024)
  • Author(s): Iwata Takuma、Kishikawa Takahiro、Seimiya Takahiro、Notoya Genso、Suzuki Tatsunori、Shibata Chikako、Miyakawa Yu、Odawara Nariaki、Funato Kazuyoshi、Tanaka Eri、Yamagami Mari、Sekiba Kazuma、Otsuka Motoyuki、Koike Kazuhiko、Fujishiro Mitsuhiro
  • Journal Title: Journal of Biological Chemistry Volume: 300 Issue: 3 Pages: 105742-105742
  • DOI: 10.1016/j.jbc.2024.105742
  • Peer Reviewed / Open Access
• [Journal Article] Skeletal muscle status and survival among patients with advanced biliary tract cancer (2024)
  • Author(s): Takaoka Shinya、Hamada Tsuyoshi、Takahara Naminatsu、Saito Kei、Endo Go、Hakuta Ryunosuke、Ishida Kota、Ishigaki Kazunaga、Kanai Sachiko、Kurihara Kohei、Oyama Hiroki、Saito Tomotaka、Sato Tatsuya、Suzuki Tatsunori、Suzuki Yukari、Tange Shuichi、Tokito Yurie、Tateishi Ryosuke、Nakai Yousuke、Fujishiro Mitsuhiro
  • Journal Title: International Journal of Clinical Oncology Volume: 29 Issue: 3 Pages: 297-308
  • DOI: 10.1007/s10147-023-02466-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combination of serum human satellite RNA and miR-21-5p levels as a biomarker for pancreatic cancer (2023)
  • Author(s): Seimiya Takahiro、Suzuki Tatsunori、Iwata Takuma、Kishikawa Takahiro、Sekiba Kazuma、Shibata Chikako、Ishigaki Kazunaga、Fujiwara Hiroaki、Oyama Hiroki、Kanai Sachiko、Sato Tatsuya、Nakai Yousuke、Ishibashi Rei、Moriyama Masaru、Nakagawa Ryo、Ijichi Hideaki、Otsuka Motoyuki、Koike Kazuhiko
  • Journal Title: iScience Volume: 26 Issue: 2 Pages: 106021-106021
  • DOI: 10.1016/j.isci.2023.106021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages (2022)
  • Author(s): Kato H, Tateishi K, Fujiwara H, Nakatsuka T, Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H, Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta R, Ishigaki K, Saito K, Saito T, Takahara N, Kishikawa T, Hamada T, Takahashi R, Miyabayashi K, et al.
  • Journal Title: Gastroenterology Volume: 162 Issue: 4 Pages: 1272-1287
  • DOI: 10.1053/j.gastro.2021.12.254
  • Peer Reviewed / Open Access
• [Journal Article] Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells. (2021)
  • Author(s): Suzuki T, Kishikawa T, Sato T, Takeda N, Sugiura Y, Seimiya T, Sekiba K, Ohno M, Iwata T, Ishibashi R, Otsuka M, Koike K.
  • Journal Title: Cancer Gene Ther. Volume: - Issue: 5 Pages: 505-518
  • DOI: 10.1038/s41417-021-00326-4
  • Peer Reviewed / Open Access