Live imaging of human pancreatic cancer stem cell dynamics

• Project/Area Number: 19K22619
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Kyoto University
• Principal Investigator: Seno Hiroshi 京都大学, 医学研究科, 教授 (90335266)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 膵臓 / 難治がん / がん / 癌

Outline of Research at the Start

本研究では、独自の生体「内外」ヒト膵がん実験系を用い、がん幹細胞を頂点とするヒト膵がん組織の動態を可視化する。すなわち、充実したヒト膵がんオルガノイド・ライブラリーをもとに、細胞系譜解析と二光子顕微鏡により、膵がん幹細胞の動態を可視化する。また、ヒト膵がんxenograftにおける膵がん幹細胞動態を、独自のイメージング・ウィンドウ越しに解析する。最後に、生体「内外」モデルの双方で、膵がん幹細胞の選択的排除によるヒト膵がん組織の退縮動態を確認する。

Outline of Final Research Achievements

The aim of this study was to establish in vitro and in vivo experimental systems that mimick human pancreatic cancer development process and to observe cancer "stem" cell behaviors in those systems. We established human pancreatic cancer organoids and inserted DCLK1-CreERT and CMV-LAL-tdTomato constructs to them. In these organoids and subsequently established xenografts, lineage tracing experiments showed that DCLK1-positive pancreatic cancer cells have a potential of cancer "stem" cells. Thus, DCLK1-positive pancreatic cancer cell might be a novel therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

本研究は、難治がんの代表であるヒト膵がんの発育進展過程を独自の生体内外モデルで可視化する試みである。膵がんのバイオロジーと新規治療法を探索する過程で、「マウスからヒトへ」さらに「ヒトにおける実用化」を視野に入れた知見を獲得し、発展させる可能性を有する。またDCLK1陽性がん細胞は、膵がん以外のヒト消化器がんにひろく存在している。そのため、将来的により普遍性の高い「消化器がん幹細胞標的療法」という新しい治療コンセプトへの道を拓く挑戦性も備えた研究と思われた。

Research Products

• [Int'l Joint Research] DKFZ and DKTK(ドイツ)
• [Journal Article] The role of SWI/SNF chromatin remodeling complex in pancreatic cancer. *corresponding author (2021)
  • Author(s): 2.Motoyuki Tsuda, Akihisa Fukuda, Munenori Kawai, Osamu Araki, Hiroshi Seno.
  • Journal Title: Cancer Science Volume: 112 Issue: 2 Pages: 490-497
  • DOI: 10.1111/cas.14768
  • 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
• [Journal Article] Setdb1 inhibits p53-mediated apoptosis and is required for formation of pancreatic ductal adenocarcinomas in mice. (2020)
  • Author(s): 6.Ogawa S, Fukuda A, Matsumoto Y, Hanyu Yu, Sono M, Fukunaga Y, Masuda T, Araki O, Nagao M, Yoshikawa T, Goto N, Hiramatsu Y, Tsuda M, Maruno T, Nakanishii Y, Hussein S.M, Tsuruyama T, Takaori K, Uemotoio S, Seno H.
  • Journal Title: Gastroenterology Volume: 159 Issue: 2 Pages: 682-696
  • DOI: 10.1053/j.gastro.2020.04.047
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors (2020)
  • Author(s): Yamauchi Yuki、Kodama Yuzo、Uza Norimitsu、Masuda Atsuhiro、Tatsuoka Hisato、Masui Toshihiko、Inagaki Nobuya、Uemoto Shinji、Chiba Tsutomu、Seno Hiroshi
  • Journal Title: Cancer Research Volume: 80 Issue: 17 Pages: 3620-3630
  • DOI: 10.1158/0008-5472.can-19-2232
  • Peer Reviewed / Open Access
• [Journal Article] CXCR4 in tumor epithelial cells mediates desmoplastic reaction in pancreatic ductal adenocarcinoma. (2020)
  • Author(s): Morita, T., Kodama, Y., Shiokawa, M., Kuriyama, K., Marui, S., Kuwada, T., Sogabe, Y., Matsumori, T., Kakiuchi, N., Tomono, T., Mima, A., Ueda, T., Tsuda, M., Yamauchi, Y., Nishikawa, Y., Sakuma, Y., Ota, Y., Maruno, T., Uza, N., Nagasawa, T., Chiba, T., and Seno, H.
  • Journal Title: Cancer Res. Volume: 80 Issue: 19 Pages: 4058-4070
  • DOI: 10.1158/0008-5472.can-19-2745
  • Peer Reviewed
• [Journal Article] Short educational video to improve the accuracy of colorectal polyp size estimation: Multicenter prospective study. (2020)
  • Author(s): Utsumi T, Horimatsu T, Nishikawa Y, Teramoto A, Hirata D, Iwatate M, Sano Y, Seno H.
  • Journal Title: Dig Endosc Volume: 32 Issue: 7 Pages: 1074-1081
  • DOI: 10.1111/den.13638
  • Peer Reviewed
• [Journal Article] Hes1 Is Essential in Proliferating Ductal Cell-Mediated Development of Intrahepatic Cholangiocarcinoma (2020)
  • Author(s): Matsumori T, Kodama Y, Takai A, Shiokawa M, Nishikawa Y, Matsumoto T, Takeda H, Marui S, Okada H, Hirano T, Kuwada T, Sogabe Y, Kakiuchi N, Tomono T, Mima A, Morita T, Ueda T, Tsuda M, Yamauchi Y, Kuriyama K, Sakuma Y, Ota Y, Maruno T, Uza N, Marusawa H, Kageyama R, Chiba T, Seno H.
  • Journal Title: Cancer Research Volume: 80 Issue: 23 Pages: 5305-5316
  • DOI: 10.1158/0008-5472.can-20-1161
  • Peer Reviewed
• [Journal Article] Epithelial EP4 plays an essential role in maintaining homeostasis in colon. (2019)
  • Author(s): Matsumoto Y, Nakanishi Y, Yoshioka T, Yamaga Y, Masuda T, Fukunaga Y, Sono M, Yoshikawa T, Nagao M, Araki O, Ogawa S, Goto N, Hiramatsu Y, Breyer RM, Fukuda A, Seno H.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 15244-15244
  • DOI: 10.1038/s41598-019-51639-2
  • NAID: 120006956728
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells. (2019)
  • Author(s): Goto N, Fukuda A, Yamaga Y, Yoshikawa T, Maruno T, Maekawa H, Inamoto S, Kawada K, Sakai Y, Miyoshi H, Taketo MM, Chiba T, Seno H.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 116 Issue: 26 Pages: 12996-13005
  • DOI: 10.1073/pnas.1900251116
  • Peer Reviewed / Open Access
• [Journal Article] Hes1 plays an essential role in Kras-driven pancreatic tumorigenesis (2019)
  • Author(s): Nishikawa Y、Kodama Y、Shiokawa M、Matsumori T、Marui S、Kuriyama K、Kuwada T、Sogabe Y、Kakiuchi N、Tomono T、Mima A、Morita T、Ueda T、Tsuda M、Yamauchi Y、Sakuma Y、Ota Y、Maruno T、Uza N、Uesugi M、Kageyama R、Chiba T、Seno H
  • Journal Title: Oncogene Volume: in press Issue: 22 Pages: 4283-4296
  • DOI: 10.1038/s41388-019-0718-5
  • Peer Reviewed / Open Access
• [Journal Article] Bmi1 marks gastric stem cells located in the isthmus in mice. (2019)
  • Author(s): Yoshioka T, Fukuda A, Araki O, Ogawa S, Hanyu Y, Matsumoto Y, Yamaga Y, Nakanishi Y, Kawada K, Sakai Y, Chiba T, Seno H.
  • Journal Title: J Pathol. Volume: 248 Issue: 2 Pages: 179-190
  • DOI: 10.1002/path.5244
  • Peer Reviewed
• [Presentation] Bmi1 is required for pancreatic cancer formation through regulating PI3K/AKT pathway in mice. (2020)
  • Author(s): Makoto Sono, Akihisa Fukuda, Motoyuki Tsuda, Hiroshi Seno
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] KrasおよびWntシグナルは幽門腺型胆嚢腺腫BilINの形成に重要である (2020)
  • Author(s): 長尾宗政、福田晃久、尾松万悠紀、並川実桜、薗誠、福永裕一、益田朋典、荒木理、吉川貴章、小川智、平松由紀子、津田喬之、丸野貴 久、中西祐貴、妹尾浩
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Brg1, a subunit of the SWI/SNF complex, is critical for growth and metastasis of pancreatic cancer cells in mice. (2020)
  • Author(s): Osamu Araki, Akihisa Fukuda, Motoyuki Tsuda, Hiroshi Seno
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Setdb1 deletion protects against formation of pancreatic ductal adenocarcinoma by inducing p53-mediated apoptosis. (2020)
  • Author(s): Satoshi Ogawa, Akihisa Fukuda, Araki Osamu, Munemasa Nagao, Takaaki Yoshikawa, Yukiko Hiramatsu, Motoyuki Tsuda, Takahisa Maruno, Yuki Nakanishi, Hiroshi Seno
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Intestinal tumor stem cell specific ablation of Brg1 resulted in reduction of intestinal tumors with increased apoptosis. (2020)
  • Author(s): Takaaki Yoshikawa, Akihisa Fukuda, Hiroshi Seno
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] KrasおよびWntシグナルは幽門腺型胆嚢腺腫，幽門腺形質をもつBilINの形成に重要である (2020)
  • Author(s): 長尾宗政、福田晃久、妹尾浩
  • Organizer: 第28回日本消化器関連学会週間
• [Presentation] SETDB1 IS REQUIRED FOR FORMATION OF PANCREATIC DUCTAL ADENOCARCINOMA BY INHIBITING APOPTOSIS THROUGH REGULATION OF P53 EXPRESSION. (2020)
  • Author(s): Satoshi Ogawa, Akihisa Fukuda, Araki Osamu, Munemasa Nagao, Takaaki Yoshikawa, Yukiko Hiramatsu, Motoyuki Tsuda, Takahisa Maruno, Yuki Nakanishi, Hiroshi Seno
  • Organizer: 51st Annual Meeting of the American Pancreatic Association
  • Int'l Joint Research
• [Presentation] The role of tuft cell-like tumor/cancer cells in intestinal tumors. (2019)
  • Author(s): 妹尾浩、後藤規弘、福田晃久
  • Organizer: 第78回日本癌学会総会
  • Invited
• [Remarks] 京都大学消化器内科ホームページ
  • URL: https://www.kuhp.kyoto-u.ac.jp/~gastro/