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

• Project/Area Number: 19K16712
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kyoto 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: ¥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。

Research Products

• [Int'l Joint Research] SBP Medical Discovery Institute(米国)
• [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] Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population (2021)
  • 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
• [Journal Article] Solitary Colorectal Metastasis from a Mucin-rich Ovarian Tumor (2020)
  • 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
• [Journal Article] Spontaneous regression of mismatch repair‐deficient colorectal cancers: Case series (2020)
  • 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
• [Journal Article] PKCλ/ι Loss Induces Autophagy, Oxidative Phosphorylation, and NRF2 to Promote Liver Cancer Progression (2020)
  • 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
• [Journal Article] Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intra-epithelial lymphocytes in the intestine (2019)
  • 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
  • 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
• [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] 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] 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
• [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
• [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
• [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
• [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
• [Presentation] Simultaneous Loss of Both Atypical Protein Kinase C Drives Serrated Intestinal Cancer with Mesenchymal Activation and Immunosuppression (2019)
  • Author(s): Yuki Nakanishi, Angeles Duran, Antoine L’Hemitte, Maria T. Diaz-Meco, Jorge Moscat
  • Organizer: American Gastroenterological Association
  • Int'l Joint Research
• [Presentation] A combination immunotherapy targetingimmunosuppression and stromal phenotypes of aggressive serrated intestinal cancer (2019)
  • Author(s): Yuki Nakanishi, Hiroshi Seno
  • Organizer: 第78回日本癌学会学術総会
  • 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
• [Patent(Industrial Property Rights)] MODELS AND METHODS USEFUL FOR THE TREATMENT OF SERRATED COLORECTAL CANCER (2019)
  • Inventor(s): Yuki Nakanishi
  • Industrial Property Rights Holder: Yuki Nakanishi
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Overseas