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

• 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
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 胆管癌 / IL-33 / オルガノイド / 胆管周囲付属腺 / マウスモデル / 肝外胆管癌

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.

Research Products

• [Journal Article] Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands. (2017)
  • Author(s): Nakagawa H, Suzuki N, Hirata Y, Hikiba Y, Hayakawa Y, Kinoshita H, Ihara S, Uchino K, Nishikawa Y, Ijichi H, Otsuka M, Arita J, Sakamoto Y, Hasegawa K, Kokudo N, Tateishi K, Koike K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114(19) Issue: 19
  • DOI: 10.1073/pnas.1619416114
  • Peer Reviewed / Open Access