Indentification of cancer initiating cells using a mouse model of cholangitis-associated cholangiocarcinoma

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09039
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: Uchino Koji 東京大学, 医学部附属病院, 助教 (00748725)
• Co-Investigator(Kenkyū-buntansha): 中川 勇人 東京大学, 医学部附属病院, その他 (00555609)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 胆管癌 / IL-33 / オルガノイド / 胆管周囲付属腺

Outline of Final Research Achievements

Based on the frequent mutations of Ras and TGFb pathways in ECC, we generated mice with tamoxifen-inducible duct cell-specific Kras activation and TGFbR2 deletion by crossing LSL-KrasG12D, Tgfbr2flox/flox, and K19CreER mice (KT-K19CreER). However, KT-K19CreER mice did not develop biliary tumors. Next, to analyze the additional effect of E-cadherin loss, KT-K19CreER mice were crossed with CDH1flox/flox mice (KTC-K19CreER). KTC-K19CreER mice developed invasive periductal infiltrating ECC within 4 weeks. Time-course analysis revealed that recombined biliary epithelial cells (BECs) lining the bile duct lumen died due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs). Dying BECs released IL-33 and stimulated a regeneration by PBGs via type 2 innate lymphoid cells, eventually leading to ECC. Cell lineage tracing suggested PBGs as the cellular origin of ECC. This mouse model provides new insight into biliary injury-based ECC development.

Free Research Field

消化器病学