Functional role of Arid1a in intestinal tumor

• Project/Area Number: 20K22841
• 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: Hayashi (Hiramatsu) Yukiko 京都大学, 医学研究科, 医員 (60876184)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 大腸癌 / エピジェネティクス / Arid1a

Outline of Research at the Start

①Conventional & Alternative 経路におけるマウス腸腫瘍モデルを用いて腸腫瘍形成・維持におけるArid1aの機能的役割をin vivoで明らかにする。
②網羅的遺伝子発現解析・ChIP解析により、それぞれの経路におけるArid1aのエピジェネティックな分子制御機構を明らかにする。
③マウス腸腫瘍オルガノイドを用いて、Arid1aとの合成致死性が報告されているEZH1/2阻害剤、ATR阻害剤、PI3K/AKT阻害剤を候補とした薬剤感受性試験を行う。
④ヒト腸腫瘍細胞からオルガノイドを樹立し、ヒト腸腫瘍におけるARID1Aの発現解析、新規薬剤開発を行う。

Outline of Final Research Achievements

We generate and investigate the mouse model in Wnt depending tumor pathway and Wnt independing tumor pathway.
In Wnt depending pathway, Arid1a plays an essential role in intestinal tumor cells for the maintenance of established intestinal tumors in a mouse model. RT-qPCR analysis revealed that Wnt signaling is depressed in Arid1a conditional knock out mice.
In contrast, in Wnt independing pathway, ross of Arid1a suppresses intestinal tumor cells. Arid1a also plays a pivotal role in cell survival and stemness in human CRC cells. Thus, Arid1a represents a new therapeutic target for human CRC.

Academic Significance and Societal Importance of the Research Achievements

これまでの結果から、Arid1aは腸腫瘍発生経路によって異なる役割を果たしている可能性が示唆された。マウスモデルで得られた知見を基に、ヒト大腸腫瘍における治療ターゲットとなり得る候補因子を導き出し、ヒト大腸腫瘍の治療戦略を大きく発展させることが期待される。加えて、申請者らが膵癌におけるArid1aの機能解析で得られた知見と比較することで、大腸腫瘍だけでなく、膵癌における治療戦略につながる可能性がある。

Research Products

• [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
• [Journal Article] Brg1 is required to maintain colorectal cancer stem cells (2021)
  • Author(s): Yoshikawa Takaaki、Fukuda Akihisa、Omatsu Mayuki、Namikawa Mio、Sono Makoto、Fukunaga Yuichi、Masuda Tomonori、Araki Osamu、Nagao Munemasa、Ogawa Satoshi、Masuo Kenji、Goto Norihiro、Hiramatsu Yukiko、Muta Yu、Tsuda Motoyuki、Maruno Takahisa、Nakanishi Yuki、Kawada Kenji、Takaishi Shigeo、Seno Hiroshi
  • Journal Title: The Journal of Pathology Volume: 255 Issue: 3 Pages: 257-269
  • DOI: 10.1002/path.5759
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging (2021)
  • Author(s): Maruno Takahisa、Fukuda Akihisa、Goto Norihiro、Tsuda Motoyuki、Ikuta Kozo、Hiramatsu Yukiko、Ogawa Satoshi、Nakanishi Yuki、Yamaga Yuichi、Yoshioka Takuto、Takaori Kyoichi、Uemoto Shinji、Saur Dieter、Chiba Tsutomu、Seno Hiroshi
  • Journal Title: eLife Volume: 10 Pages: 1-24
  • DOI: 10.7554/elife.55117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 小腸におけるArid1aの機能的役割 (2020)
  • Author(s): 平松由紀子
  • Organizer: 日本消化器病学会