Visualization and molecular analysis of cholangiocarcinogenesis pathway by mitochondrial photoactivity
| Project/Area Number |
20K08277
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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 | The University of Tokyo |
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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)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 胆管癌 / 胆道癌 / 5-ALA / 光線力学的診断 / エピジェネテイクス / 肝内胆管癌 |
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| Outline of Research at the Start |
胆管癌の診断治療には未だ課題が多いが、今回胆管癌患者由来の腫瘍部と隣接非腫瘍部のそ
れぞれの組織から樹立したオルガノイドを用いて、胆管癌細胞が光活性を呈することを見出した。この活性は非腫瘍部胆管細胞では認められず癌特異的であった。本研究ではこのオルガノイドにおける光活性を指標として、遺伝子変異蓄積による胆管細胞の癌化過程を可視化・解析するツールとして活用する。
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| Outline of Final Research Achievements |
The molecular characteristics of cholangiocarcinoma remain unclear. The definitive driver mutations for therapeutic target molecules are not yet known. Although KRAS, SMAD4, ARID1A, GNAS, ELF3, and ARID1B have been reported as candidate driver genes for extrahepatic cholangiocarcinoma, the contribution of each mutation to carcinogenesis has not been fully investigated.
In this study, we found that cholangiocarcinoma cells exhibit 5-ALA-dependent photoactivity. This activity was cancer-specific. We investigated the expression of components of intracellular porphyrin metabolism and related epigenetic dysregulation as the cause of 5-ALA-dependent photoactivity in cholangiocarcinoma. In parallel, candidate driver mutations found in cholangiocarcinoma were introduced into nonneoplastic cholangiocytes and evaluated for induction of tumorigenesis using 5-ALA-dependent photoactivity as an indicator.
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| Academic Significance and Societal Importance of the Research Achievements |
これまでヒト胆管癌の研究ツールとしては数少ない細胞株に限られ、症例ごとの進展様式の違いを反映する細胞モデルや、正常・前がん状態の胆管細胞の培養系も存在しなかった。本研究では倫理委員会の承認のもと、胆管癌患者由来の腫瘍部と隣接非腫瘍部のそれぞれの組織からオルガノイド培養系を樹立することに成功した。このオルガノイドモデルを遺伝子変異の蓄積と胆管癌発生過程との相関を可視化・解析するツールとして活用した結果、新たな胆管癌に対する治療概念につながる成果を得つつある。
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Report
(4 results)
Research Products
(1 results)
