Therapeutic strategy against gastrointestinal cancer by utilizing cancer hierarchy

• Project/Area Number: 17H04157
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: Seno Hiroshi 京都大学, 医学研究科, 教授 (90335266)
• Co-Investigator(Kenkyū-buntansha): 福田 晃久 京都大学, 医学研究科, 講師 (70644897)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000); Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 大腸癌 / 膵臓癌 / 可塑性 / 分化 / 癌 / 内科

Outline of Final Research Achievements

During cancer development, cancer stem cells are closely associated with hierarchy and plasticity of cancer tissues. Previously, we reported that Dclk1 is one of the cancer stem cell-specific markers, and that SWI/SNF complex regulates differentiation of gastrointestinal cancers. Based on these findings, we here investigated (1) therapeutic strategy by utilizing cancer hierarchy and cancer stem cells, (2) therapeutic strategy by focusing on plasticity and differentiation status, and (3) detrermined them in organoid and patient-derived xenograft systems. These experiments indicated fundamental data to develop novel therapeutic strategies against various gastrointestinal cancers.

Academic Significance and Societal Importance of the Research Achievements

本研究を通じて、正常組織への傷害を回避しつつ癌組織を選択的に退縮させる理想的な癌治療へ近づくための基礎的知見を得ることができた。また、可塑性を応用した分化誘導治療に道を拓き、臓器の違いを超えた消化器癌治療の開発につながる将来性が期待される。このように、消化器癌の階層性と可塑性の本態に迫ろうとする学術的側面と、ヒト消化器癌の生体外可視化モデルを併用して「消化器癌幹細胞標的・分化誘導治療法開発」へ向けた創薬標的を検証する臨床的側面の双方で意義を有する研究と思われた。

Research Products

• [Journal Article] Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis (2019)
  • Author(s): Kakiuchi Nobuyuki et al.
  • Journal Title: Nature Volume: 577 Issue: 7789 Pages: 260-265
  • DOI: 10.1038/s41586-019-1856-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Journal Article] Arid1a is essential for intestinal stem cells through Sox9 regulation. (2019)
  • Author(s): Hiramatsu Y, Fukuda A, Ogawa S, Goto N, Ikuta K, Tsuda M, Matsumoto Y, Kimura Y, Yoshioka T, Takada Y, Maruno T, Hanyu Y, Tsuruyama T, Wang Z, Akiyama H, Takaishi S, Miyoshi H, Taketo MM, Chiba T, Seno H.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 116 (5) Issue: 5 Pages: 1704-1713
  • DOI: 10.1073/pnas.1804858116
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis. (2018)
  • Author(s): Tsuda M, Fukuda A, Roy N, Hiramatsu Y, Leonhardt L, Kakiuchi N, Hoyer K, Ogawa S, Goto N, Ikuta K, Kimura Y, Matsumoto Y, Takada Y, Yoshioka T, Maruno T, Yamaga Y, Kim GE, Akiyama H, Ogawa S, Wright CV, Saur D, Takaori K, Uemoto S, Hebrok M, Chiba T, Seno H.
  • Journal Title: J Clin Invest. Volume: 128 Issue: 8 Pages: 3475-3489
  • DOI: 10.1172/jci94287
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene expression profile of Dclk1+ cells in intestinal tumors. (2018)
  • Author(s): Yamaga Y, Fukuda A, Nakanishi Y, Goto N, Matsumoto Y, Yoshioka T, Maruno T, Chiba T, Seno H.
  • Journal Title: Dig Liver Dis. Volume: 50 Issue: 12 Pages: 1353-1361
  • DOI: 10.1016/j.dld.2018.06.011
  • Peer Reviewed
• [Journal Article] ARID1A Maintains Differentiation of Pancreatic Ductal Cells and inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice (2018)
  • Author(s): Yoshito Kimura, Akihisa Fukuda, Satoshi Ogawa, Takahisa Maruno, Yutaka Takada, Motoyuki Tsuda, Yukiko Hiramatsu, Osamu Araki, Munemasa Nagao, Takaaki Yoshikawa, Kozo Ikuta, Takuto Yoshioka, Zong Wang, Haruhiko Akiyama, Christopher V. Wright, Kyoichi Takaori, Shinji Uemoto, Tsutomu Chiba, Hiroshi Seno
  • Journal Title: Gastroenterology Volume: 3 Issue: 1 Pages: 30346-9
  • DOI: 10.1053/j.gastro.2018.03.039
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chemokine CXCL16 mediates acinar cell necrosis in cerulein induced acute pancreatitis in mice. (2018)
  • Author(s): Sakuma Y, Kodama Y, Eguchi T, Uza N, Tsuji Y, Shiokawa M, Maruno T, Kuriyama K, Nishikawa Y, Yamauchi Y, Tsuda M, Ueda T, Matsumori T, Morita T, Tomono T, Kakiuchi N, Mima A, Sogabe Y, Marui S, Kuwada T, Okada A, Watanabe T, Nakase H, Chiba T, Seno H.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 8829-8829
  • DOI: 10.1038/s41598-018-27200-y
  • NAID: 120006532078
  • Peer Reviewed / Open Access
• [Journal Article] Nardilysin controls intestinal tumorigenesis through HDAC1/p53?dependent transcriptional regulation (2018)
  • Author(s): Kanda Keitaro、Sakamoto Jiro、Matsumoto Yoshihide、Ikuta Kozo、Goto Norihiro、Morita Yusuke、Ohno Mikiko、Nishi Kiyoto、Chiba Tsutomu、Nishi Eiichiro、Seno Hiroshi
  • Journal Title: JCI Insight Volume: 3 Issue: 8 Pages: 1-15
  • DOI: 10.1172/jci.insight.91316
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of Mac-2-binding protein glycosylation isomer level with nutritional status in chronic liver disease (2018)
  • Author(s): Eso Yuji、Takai Atsushi、Taura Kojiro、Takahashi Ken、Ueda Yoshihide、Marusawa Hiroyuki、Seno Hiroshi
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 印刷中 Issue: 9 Pages: 1649-1658
  • DOI: 10.1111/jgh.14130
  • Peer Reviewed
• [Journal Article] Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine (2017)
  • Author(s): Goto Norihiro、Ueo Taro、Fukuda Akihisa、Kawada Kenji、Sakai Yoshiharu、Miyoshi Hiroyuki、Taketo Makoto Mark、Chiba Tsutomu、Seno Hiroshi
  • Journal Title: Cancer Research Volume: 77 Issue: 13 Pages: 3442-3454
  • DOI: 10.1158/0008-5472.can-16-3192
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma (2017)
  • Author(s): Matsumoto Tomonori、Takai Atsushi、Eso Yuji、Kinoshita Kazuo、Manabe Toshiaki、Seno Hiroshi、Chiba Tsutomu、Marusawa Hiroyuki
  • Journal Title: Cancer Research Volume: 77 Issue: 22 Pages: 6131-6143
  • DOI: 10.1158/0008-5472.can-17-1800
  • Peer Reviewed
• [Journal Article] Tumor invasion to the arteries feeding the gallbladder as a novel risk factor for cholecystitis after metallic stent placement in distal malignant biliary obstruction (2017)
  • Author(s): Sogabe Yuko、Kodama Yuzo、Honjo Hajime、Aoyama Ikuo、Kawanami Chiharu, Seno Hiroshi, et al.
  • Journal Title: Digestive Endoscopy Volume: 印刷中 Issue: 3 Pages: 380-387
  • DOI: 10.1111/den.12991
  • NAID: 130007569115
  • Peer Reviewed
• [Journal Article] Utility of KRAS mutational analysis in the preoperative diagnosis of synchronous pancreatic cancer and intrahepatic cholangiocarcinoma (2017)
  • Author(s): Eso Yuji、Uza Norimitsu、Yamagishi Hiroko、Imada Kazuaki、Kimura Yuto、Masui Toshihiko、Kodama Yuzo、Seno Hiroshi
  • Journal Title: Medicine Volume: 96 Issue: 50 Pages: e9217-e9217
  • DOI: 10.1097/md.0000000000009217
  • Peer Reviewed / Open Access
• [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
• [Presentation] Sox9制御を介した腸幹細胞、腸恒常性維持におけるArid1aの役割について (2018)
  • Author(s): 平松由紀子、福田晃久、妹尾浩
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] The functional role of Eset in exocrine pancreatic regeneration and pancreatic cancer initiation (2018)
  • Author(s): 小川智、福田晃久、津田喬之、後藤規弘、平松由紀子、妹尾浩
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis. (2018)
  • Author(s): 津田喬之、福田晃久、妹尾浩
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Essential role of Arid1a in intestinal stem cell maintenance and homeostasis through Sox9 regulation. (2018)
  • Author(s): Yukio Hiramatsu, Akihisa Fukuda, Hiroshi Seno
  • Organizer: GI Research Academy 2018
  • Int'l Joint Research
• [Presentation] 腸管の正常幹細胞と腫瘍幹細胞におけるHes1の役割 (2018)
  • Author(s): 後藤規弘、福田晃久、妹尾浩
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] The role of Hes1 in the normal and tumor stem cells of the intestine. (2017)
  • Author(s): Norihiro Goto, Akihisa Fukuda, Tsutomu Chiba, Hiroshi Seno
  • Organizer: American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] Brg1 plays a critical role in PanIN formation through regulating Sox9 expression. (2017)
  • Author(s): Motoyuki Tsuda, Akihisa Fukuda, Takahisa Maruno, Haruhiko Akiyama, Kyoichi Takaori, Shinji Uemoto, Tsutomu Chiba, Hiroshi Seno, et al.
  • Organizer: American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] EpCAM陽性肝幹/前駆細胞を起源とした肝発癌の分子機構 (2017)
  • Author(s): 松本知訓、妹尾浩、丸澤宏之
  • Organizer: 第103回日本消化器病学会総会
• [Presentation] Nardilysin functions as a tumor suppressor in pancreatic ductal adenocarcinoma through maintaining acinar cell differentiation and suppressing pancreatitis. (2017)
  • Author(s): Kozo Ikuta, Akihisa Fukuda, Eiichiro Nishi, Hiroshi Seno, et al.
  • Organizer: Digestive Disease Week 2017
  • Int'l Joint Research
• [Presentation] 膵がん形成過程における可塑性と幹細胞性 (2017)
  • Author(s): 妹尾浩、丸野貴久、後藤規弘、津田喬之、木村佳人、福田晃久
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Remarks] 京都大学大学院医学研究科・消化器内科学 研究業績2018年
  • URL: https://www.kuhp.kyoto-u.ac.jp/~gastro/kenkyu/gyoseki.html