NK cell resistance acquisition in MSS colorectal cancer

• Project/Area Number: 19K17478
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Suzuki Nobumi 東京大学, 医学部附属病院, 助教 (30723746)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 大腸癌 / NKcell / 大腸がん / オルガノイド

Outline of Research at the Start

本研究では、MSS大腸癌に対するNKcell療法を可能性を検証するために、マウス正常細胞の培養を可能としたオルガノイド培養技術を使用して、連続的にAPC,Kras,Braf,p53,p16,RNF43,ZNRF3,SMAD4, TGFBR2等の遺伝子変異を連続的に加えることで、各々異なった遺伝的特徴をもった大腸癌オルガノイドを作成し、NKcellと共培養することで、各、大腸癌オルガノイドがどのようにしてNKcell耐性を獲得するのかを解明することを目指します。

Outline of Final Research Achievements

In this study, we created genetically modified mouse colorectal organoids that mimic MSS and MSI-H colorectal cancer by CRSIPR / Cas9, in order to elucidate the mechanism which colorectal cancer acquires resistance to NK cells (natural killer cells). When cancerous organoids were co-cultured with NK cells, MSS organoids were sensitive to NK cells. MSI-H cancerous organoids had acquired resistance to NK cells. To verify the involvement of the TGF / Smad pathway in resistance acquisition, we added genetic modifications to MSS organoids that cause abnormalities in the TGF / Smad pathway, but susceptibility to NK cells remained maintained.

Academic Significance and Societal Importance of the Research Achievements

近年、免疫チェックポイント阻害剤の実用化に伴い、大腸癌でも同阻害剤の使用が進んでいる。しかし、既存の免疫チェックポイント阻害剤は、固形癌ではMSI-Hに分類される一部の癌にしか奏功しないことが、近年明らかになった。大腸癌でMSI-Hと分類されるのはおおよそ10％以下とされており、多くの大腸癌には無効である。本研究では、MSS、MSI-HのB6マウス大腸癌オルガノイド株を作成した。生物学研究において最も頻用されているB6近交系マウス由来のオルガノイド株を作成できたことは、NKcellに関連する免疫研究においては、MHCclass1が同一であることが重要であることか、今後の研究に有用と考えられる。

Research Products

• [Journal Article] Delineating proinflammatory microenvironmental signals by ex vivo modeling of the immature intestinal stroma (2021)
  • Author(s): Ichinose Mari、Suzuki Nobumi、Wang Tongtong、Wright Josephine A.、Lannagan Tamsin R. M.、Vrbanac Laura、Kobayashi Hiroki、Gieniec Krystyna、Ng Jia Q.、Ihara Souzaburo、Mavrangelos Chris、Hayakawa Yoku、Hughes Patrick、Worthley Daniel L.、Woods Susan L.
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-86675-4
• [Journal Article] Stromal DLK1 promotes proliferation and inhibits differentiation of the intestinal epithelium during development (2021)
  • Author(s): Ichinose Mari、Suzuki Nobumi、et al.
  • Journal Title: American Journal of Physiology-Gastrointestinal and Liver Physiology Volume: 320 Issue: 4 Pages: 506-520
  • DOI: 10.1152/ajpgi.00445.2020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Axin2+ Peribiliary Glands in the Periampullary Region Generate Biliary Epithelial Stem Cells That Give Rise to Ampullary Carcinoma (2021)
  • Author(s): Hayata Yuki、Nakagawa Hayato、Kurosaki Shigeyuki、Kawamura Satoshi、Matsushita Yuki、Hayakawa Yoku、Suzuki Nobumi、Hata Masahiro、Tsuboi Mayo、Kinoshita Hiroto、Miyabayashi Koji、Mizutani Hiroya、Nakagomi Ryo、Ikenoue Tsuneo、Hirata Yoshihiro、Arita Junichi、Hasegawa Kiyoshi、Tateishi Keisuke、Koike Kazuhiko
  • Journal Title: Gastroenterology Volume: 160 Issue: 6 Pages: 2133-2148.e6
  • DOI: 10.1053/j.gastro.2021.01.028
• [Journal Article] Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection. (2020)
  • Author(s): Hayakawa, Y.; Hirata, Y.; Hata, M.; Tsuboi, M.; Oya, Y.; Kurokawa, K.; Abe, S.; Arai, J.; Suzuki, N.; Nakagawa, H.; Fujiwara, H.; Tateishi, K.; Maeda, S.; Koike, K
  • Journal Title: Microorganisms Volume: 8 Issue: 12 Pages: 1-20
  • DOI: 10.3390/microorganisms8121995
  • Peer Reviewed / Open Access
• [Journal Article] Mouse Model for Cholangiocarcinoma from Peribiliary Glands. (2019)
  • Author(s): Nakagawa H, Suzuki N, Koike K.
  • Journal Title: Methods Mol Biol. Volume: 1905 Pages: 237-245
  • DOI: 10.1007/978-1-4939-8961-4_21
  • ISBN: 9781493989607, 9781493989614
  • Peer Reviewed
• [Journal Article] Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation (2019)
  • Author(s): Fujiwara H、Tateishi K、Misumi K、Hayashi A、Igarashi K、Kato H、Nakatsuka T、Suzuki N、Yamamoto K、Kudo Y、Hayakawa Y、Nakagawa 、Tanaka Y、Ijichi H、Kogure H、Nakai Y、Isayama H、Hasegawa K、Fukayama M、Soga T、Koike K
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 18859-18859
  • DOI: 10.1038/s41598-019-55211-w
  • Peer Reviewed / Open Access
• [Journal Article] Alpha-Blockers As Colorectal Cancer Chemopreventive: Findings from a Case?Control Study, Human Cell Cultures, and In Vivo Preclinical Testing (2019)
  • Author(s): Suzuki Nobumi、Niikura Ryota、Ihara Sozaburo、Hikiba Yohko、Kinoshita Hiroto、Higashishima Naoko、Hayakawa Yoku、Yamada Atsuo、Hirata Yoshihiro、Nakata Ryo、Okamoto Makoto、Sano Munetaka、Kushiyama Akifumi、Ichinose Mari、Woods Susan L.、Worthley Daniel、Iwamoto Yasuhiko、Koike Kazuhiko
  • Journal Title: Cancer Prevention Research Volume: 12 Issue: 3 Pages: 185-194
  • DOI: 10.1158/1940-6207.capr-18-0288
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis (2018)
  • Author(s): Lannagan Tamsin R M、,,,、Hayakawa Yoku,,, Worthley Daniel L、Woods Susan L
  • Journal Title: Gut Volume: 68 Issue: 4 Pages: 684-692
  • DOI: 10.1136/gutjnl-2017-315920
  • Peer Reviewed / Int'l Joint Research
• [Presentation] A novel mouse model of Gastric Adenocarcinoma andProximal Polyposis of the Stomach (GAPPS) mimics the human disease. (2019)
  • Author(s): Nobumi Suzuki
  • Organizer: AGITG Annual Scientific Meeting, 2019
  • Int'l Joint Research