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

2023 Fiscal Year Final Research Report

• 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
• Keywords: 膵がん

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.

Free Research Field

消化器内科学

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。