2020 Fiscal Year Final Research Report
Dissecting cancer biology with reprogramming technology
Project/Area Number |
18H04026
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Medium-sized Section 49:Pathology, infection/immunology, and related fields
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Research Institution | The University of Tokyo |
Principal Investigator |
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Project Period (FY) |
2018-04-01 – 2021-03-31
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Keywords | 発癌 |
Outline of Final Research Achievements |
Cancer cells often exhibit dedifferentiation. However, the causal role of the dedifferentiation on cancer development has not been unequivocally demonstrated. In this project, taking advantage of the reprogramming technology and mouse genetics, we demonstrated that dedifferentiation indeed plays a crucial role in the development of Kras-mediated pancreatic ductal adenocarcinoma. We show that the transient expression of reprogramming factors results in the transient dedifferentiation. Mechanistically, repression of enhancers causes the dedifferentiation, which is similarly observed in pancreatitis. In contrast, the forced maintenance of enhancers inhibits the pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells. These results underscore a crucial role of dedifferentiation-associated epigenetic regulations in the initiation of pancreatic cancers.
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Free Research Field |
腫瘍病理学
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Academic Significance and Societal Importance of the Research Achievements |
我が国の死因の約1/3はがんによる。なかでも膵癌は有効な治療法がなく最も予後が悪いがんである。本研究では、膵癌発生の新たなメカニズムを提唱した。また、がんの原因は遺伝子変異の蓄積であると考えられているが、本研究により、遺伝子配列の異常のみならず周囲環境の変化に応じたエピゲノム制御の変化が非常に重要であることを示した。さらに、細胞の脱分化に関わるエピゲノムを標的としたがん治療の可能性を提示した。
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