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Cancer stem cell targeting therapy for colorectal cancer by regulating a factor involved in the control of immunogenicity

Research Project

Project/Area Number 19K16712
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionKyoto University

Principal Investigator

Nakanishi Yuki  京都大学, 医学研究科, 特定助教 (40838679)

Project Period (FY) 2019-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords大腸癌 / 癌幹細胞 / 癌免疫療法 / 転移
Outline of Research at the Start

癌免疫療法はほとんどの大腸癌において有効性が認められていない。免疫治療抵抗性の原因の究明が急がれるが、その機序は未だ十分に解明されていない。本研究では、マウス・ヒト双方の癌オルガノイドを用いた直腸局所・肝転移巣モデルにより、ヒト転移性大腸癌に類似したモデルで癌幹細胞の性質・機能分析を行う予定である。同モデルにICD誘導もしくは阻害剤と遺伝子編集技術、さらには既存の免疫チェックポイント阻害剤を併用することで、癌幹細胞による腫瘍免疫原性制御メカニズムを解明するとともに、腫瘍免疫原性調節による大腸癌新規治療法への発展を目指す。

Outline of Final Research Achievements

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Immunotherapy could be a viable option for patients with cancers; however, most CRCs (MSS CRCs), except those with MSI-high CRCs, respond poorly to immunotherapy. Through this project, we found the unresponsiveness of MSS CRC is caused, at least in part, by low immunogenicity induced by cancer stem cells. By targeting this mechanism, the new immunotherapy for CRC would be developed. We believe our proposal is highly significant and of great impact as it harbors the potential to fill a major gap in the field of immunotherapy for cancers which are resistant to current immunotherapy.

Academic Significance and Societal Importance of the Research Achievements

癌免疫療法は大腸癌に対しては、ごく少数のマイクロサテライト不安定性(MSI-high)癌を除き、大多数をしめるマイクロサテライト安定性(MSS)癌には有効性が認められていない。本研究を通じて、MSS大腸癌における免疫治療抵抗性が形成される機序解明のための基礎的知見を得ることができた。今後、同機構を標的とすることにより、大腸癌の免疫治療抵抗性を克服する新規癌免疫療法開発につながる可能性がある。また、癌幹細胞の存在が示唆される他の多くの癌種に対しても、あてはまる普遍性を持つ研究であり、本研究の知見が癌種一般に対する治療成績向上につながることが期待される。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (19 results)

All 2021 2020 2019 Other

All Int'l Joint Research (1 results) Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (8 results) (of which Int'l Joint Research: 2 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] SBP Medical Discovery Institute(米国)

    • Related Report
      2019 Research-status Report
  • [Journal Article] Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging2021

    • 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

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population2021

    • Author(s)
      Kasashima Hiroaki、Duran Angeles、Martinez-Ordo?ez Anxo、Nakanishi Yuki、Kinoshita Hiroto、Linares Juan F.、Reina-Campos Miguel、Kudo Yotaro、L’Hermitte Antoine、Yashiro Masakazu、Ohira Masaichi、Bao Fei、Tauriello Daniele V.F.、Batlle Eduard、Diaz-Meco Maria T.、Moscat Jorge
    • Journal Title

      Developmental Cell

      Volume: 56 Issue: 1 Pages: 95-110.e10

    • DOI

      10.1016/j.devcel.2020.10.014

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Solitary Colorectal Metastasis from a Mucin-rich Ovarian Tumor2020

    • Author(s)
      Utsumi Takahiro、Nakanishi Yuki、Minamiguchi Sachiko、Miyamoto Shin'ichi
    • Journal Title

      Internal Medicine

      Volume: 59 Issue: 1 Pages: 135-136

    • DOI

      10.2169/internalmedicine.3541-19

    • NAID

      130007779221

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2020-01-01
    • Related Report
      2019 Research-status Report
  • [Journal Article] Spontaneous regression of mismatch repair‐deficient colorectal cancers: Case series2020

    • Author(s)
      Utsumi Takahiro、Miyamoto Shin'ichi、Shimizu Takahiro、Yokogawa Kasumi、Nakanishi Yuki、Nikaido Mitsuhiro、Hirata Ayako、Nishida Miyu、Aoyama Ikuo、Okuno Tomoko、Yoshizawa Akihiko、Kaneda Akihiro、Sakai Yoshiharu、Kawanami Chiharu、Seno Hiroshi
    • Journal Title

      Digestive Endoscopy

      Volume: 33 Issue: 1 Pages: 190-194

    • DOI

      10.1111/den.13723

    • Related Report
      2020 Annual Research Report
  • [Journal Article] PKCλ/ι Loss Induces Autophagy, Oxidative Phosphorylation, and NRF2 to Promote Liver Cancer Progression2020

    • Author(s)
      Kudo Yotaro、Sugimoto Masayuki、Arias Esperanza、Kasashima Hiroaki、Cordes Thekla、Linares Juan F.、Duran Angeles、Nakanishi Yuki、Nakanishi Naoko、L'Hermitte Antoine、Campos Alex、Senni Nadia、Rooslid Tarmo、Roberts Lewis R.、Cuervo Ana Maria、Metallo Christian M.、Karin Michael、Diaz-Meco Maria T.、Moscat Jorge
    • Journal Title

      Cancer Cell

      Volume: 38 Issue: 2 Pages: 247-262.e11

    • DOI

      10.1016/j.ccell.2020.05.018

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intra-epithelial lymphocytes in the intestine2019

    • Author(s)
      Zhu Yuanbo、Cui Guangwei、Miyauchi Eiji、Nakanishi Yuki、Mukohira Hisa、Shimba Akihiro、Abe Shinya、Tani-ichi Shizue、Hara Takahiro、Nakase Hiroshi、Chiba Tsutomu、Sehara-Fujisawa Atsuko、Seno Hiroshi、Ohno Hiroshi、Ikuta Koichi
    • Journal Title

      International Immunology

      Volume: 32 Issue: 5 Pages: 307-319

    • DOI

      10.1093/intimm/dxz082

    • NAID

      120006846480

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Serrated Colorectal Cancer: The Road Less Travelled?2019

    • Author(s)
      Nakanishi Yuki、Diaz-Meco Maria T.、Moscat Jorge
    • Journal Title

      Trends in Cancer

      Volume: 5 Issue: 11 Pages: 742-754

    • DOI

      10.1016/j.trecan.2019.09.004

    • Related Report
      2019 Research-status Report
  • [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

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] Setdb1を欠損するとp53依存性アポトーシスが誘導されて膵臓癌形成が阻害される2020

    • Author(s)
      小川智, 福田晃久, 荒木理, 長尾宗政, 吉川貴章, 平松由紀子, 津田喬之, 丸野貴久, 中西祐貴, 妹尾浩
    • Organizer
      日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 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2020

    • Author(s)
      KrasおよびWntシグナルは幽門腺型胆嚢腺腫の形成に重要である
    • Organizer
      日本癌学会学術総会抄録集
    • Related Report
      2020 Annual Research Report
  • [Presentation] 吉川貴章, 福田晃久, 荒木理, 長尾宗政, 小川智, 平松由紀子, 津田喬之, 丸野貴久, 中西祐貴, 妹尾浩2020

    • Author(s)
      腸腫瘍幹細胞特異的なBrg1のノックアウトによりアポトーシスが誘導され,腸腫瘍が退縮する
    • Organizer
      日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] SWI/SNF複合体のサブユニットであるBrg1はマウス膵癌の増殖・転移に重要である2020

    • Author(s)
      荒木理, 福田晃久, 津田喬之, 薗誠, 長尾宗政, 吉川貴章, 小川智, 平松由紀子, 丸野貴久, 中西祐貴, 妹尾浩
    • Organizer
      日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] クロマチンリモデリング因子Brg1は膵がんの増殖・転移に重要である2020

    • Author(s)
      荒木理, 福田晃久, 津田喬之, 尾松万悠紀, 並川実桜, 薗誠, 益田朋典, 福永裕一, 吉川貴章, 長尾宗政, 平松由紀子, 丸野貴久, 中西祐貴, 妹尾浩
    • Organizer
      膵臓
    • Related Report
      2020 Annual Research Report
  • [Presentation] Simultaneous Loss of Both Atypical Protein Kinase C Drives Serrated Intestinal Cancer with Mesenchymal Activation and Immunosuppression2019

    • Author(s)
      Yuki Nakanishi, Angeles Duran, Antoine L’Hemitte, Maria T. Diaz-Meco, Jorge Moscat
    • Organizer
      American Gastroenterological Association
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] A combination immunotherapy targetingimmunosuppression and stromal phenotypes of aggressive serrated intestinal cancer2019

    • Author(s)
      Yuki Nakanishi, Hiroshi Seno
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Atypical PKC による大腸癌発生抑制機構の分子的解明と治療への応用2019

    • Author(s)
      中西祐貴
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] MODELS AND METHODS USEFUL FOR THE TREATMENT OF SERRATED COLORECTAL CANCER2019

    • Inventor(s)
      Yuki Nakanishi
    • Industrial Property Rights Holder
      Yuki Nakanishi
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Research-status Report
    • Overseas

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Published: 2019-04-18   Modified: 2023-12-25  

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