2024 Fiscal Year Final Research Report
Comprehensive analysis of epigenome addiction in intrahepatic cholangiocarcinoma
| Project/Area Number |
21K07935
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Nihon University (2022-2024)
The University of Tokyo (2021) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
立石 敬介 東京大学, 医学部附属病院, 届出研究員 (20396948)
工藤 洋太郎 東京大学, 医学部附属病院, 助教 (90608358)
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| Project Period (FY) |
2021-04-01 – 2025-03-31
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| Keywords | 肝内胆管癌 |
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| Outline of Final Research Achievements |
The molecular basis for the efficacy of molecularly targeted drugs against cancer is their ability to target oncogene addiction. Intrahepatic cholangiocarcinoma (ICC), one of the most intractable cancers, has a limited number of targetable genomic abnormalities such as IDH1 and FGFR. We reported that IDH1 mutations are responsible for upregulation of the glycolytic gene PFK1 and that IDH1 mutations increase sensitivity to the BET inhibitor JQ1 in ICCs. Epigenomic regulation, including chromatin dynamics, by IDH mutations may induce purposeful gene expression in response to chronic environmental responses.
Since ICCs have a characteristic microenvironment consisting of abundant stroma, it is possible that important and specific epigenomic alterations may be induced that link the external stimuli to survival and proliferation.
We analyzed ICC-specific chromatin structures, their biological significance and the genetic abnormalities that cooperate with IDH mutations.
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| Free Research Field |
胆道、膵臓
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| Academic Significance and Societal Importance of the Research Achievements |
本研究ではICC のDNA メチル化、ヒストン修飾とともに、クロマチン構造を解析するが、今のところ類似の報告はなされていない。現在の膵・胆道癌研究の殆どはヒト細胞株およびマウスモデルを用いるが、患者個々の癌細胞のエピゲノムプロファイルは必ずしも共通ではなく既存の細胞株では代用しえない。本研究では患者由来ICCオルガノイドを用いることで、臨床検体のクロマチン構造やその生物学的特性との相関を直接解析できる独自性を有する。またICCにおける遺伝子変異とクロマチン構造の相関は未解明であり、クロマチン構造の制御を念頭においた新たな抗腫瘍効果の分子機構を探索・提唱できる可能性を有している。
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