Visualization and molecular analysis of cholangiocarcinogenesis pathway by mitochondrial photoactivity

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08277
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Takahara Naminatsu 東京大学, 医学部附属病院, 助教 (10750622)
• 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)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 胆管癌

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.

Free Research Field

消化器病学

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。