The analysis of the functional role of Kras and canonical Wnt pathways for tumorigenesis of biliary system.

• Project/Area Number: 21K20801
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Kyoto University
• Principal Investigator: Nagao Munemasa 京都大学, 医学研究科, 客員研究員 (20907860)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 胆道癌 / 胆道腫瘍 / Wnt / Kras / 胆管癌 / 胆嚢癌

Outline of Research at the Start

申請者はこれまでにマウスの肝外胆管、胆嚢上皮においてKrasとWntシグナルの両方を同時に活性化させると、肝外胆管および胆嚢にBilINやICPNといった胆道の前癌病変が形成されることを見出した。本研究はマウスモデルと3次元培養技術を用いて、胆道腫瘍発生におけるKras、Wntシグナルの機能的役割とその分子機構の解析を行う。また、形成された腫瘍が前癌病変であるかどうかについても検討する。

Outline of Final Research Achievements

We revealed that the Hnf1bCreER mouse is a suitable CreER mouse line for genetic manipulation in the extrahepatic biliary tract epithelium including the EHBD and GB for the first time. In mice, concurrent activation of Kras and Wnt pathways induced biliary neoplasms including ICPN and BilIN. The biliary neoplasm spheroids were established and these neoplasm spheroids were subcutaneously into NOD/SCID mice. The xenograft analysis showed that ICPN and BilIN were putative precursors to invasive biliary cancer. Mechanistically, c-Myc contributed to tumorigenesis, whereas the Tgfb pathway inhibited it. These results were reported.

Academic Significance and Societal Importance of the Research Achievements

これまで世界的にも胆道腫瘍マウスモデルはほとんど報告されていなかった。我々は研究期間を通じて、胆道上皮特異的に遺伝子改変ができる遺伝子改変マウスを発見し、Kras、Wntシグナルが胆道腫瘍を発生させるメカニズムを解析し、研究結果を報告した。これらの研究手法は胆道上皮における他の分子の機能的役割について解析することに応用ができるという点では非常に意義が大きいと考える。

Research Products

• [Journal Article] p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras (2023)
  • Author(s): Nagao Munemasa、Mizukoshi Kenta、Nakayama Shinnosuke、Namikawa Mio、Hiramatsu Yukiko、Maruno Takahisa、Nakanishi Yuki、Tsuruyama Tatsuaki、Fukuda Akihisa、Seno Hiroshi
  • Journal Title: Oncotarget Volume: 14 Issue: 1 Pages: 276-279
  • DOI: 10.18632/oncotarget.28380
  • Peer Reviewed / Open Access
• [Journal Article] The role of Kras and canonical Wnt pathways for tumorigenesis of extrahepatic biliary system (2023)
  • Author(s): Nagao Munemasa、Fukuda Akihisa、Seno Hiroshi
  • Journal Title: Oncotarget Volume: 14 Issue: 1 Pages: 54-56
  • DOI: 10.18632/oncotarget.28349
  • Peer Reviewed / Open Access
• [Journal Article] Concurrent activation of Kras and canonical Wnt signaling induces premalignant lesions that progress to extrahepatic biliary cancer in mice (2022)
  • Author(s): Nagao M, Fukuda A, Omatsu M, Namikawa M, Sono M, Fukunaga Y, Masuda T, Araki O, Yoshikawa T, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Taketo MM, Ferrer J, Tsuruyama T, Nakanuma Y, Taura K, Uemoto S, Seno H.
  • Journal Title: Cancer Res. Volume: - Issue: 9 Pages: 1803-1817
  • DOI: 10.1158/0008-5472.can-21-2176
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Kras および WNT signaling の活性化により肝外胆管・胆嚢に前癌病変が形成され、胆道癌に進展する (2023)
  • Author(s): 長尾宗政、福田 晃久 、水越 健太、岩根 康祐、河相 宗矩、山川 剛、尾松 万悠紀、並川 実桜、薗 誠、益田 朋典、平松 由紀子、 丸野 貴久、中西 祐貴、妹尾 浩
  • Organizer: 第81回日本癌学会学術総会