Investigation of the gastric carcinogenesis using gastric tumor organoid library and artifitial cancer organoids.

• Project/Area Number: 17K15967
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: Nanki Kosaku 慶應義塾大学, 医学部(信濃町), 助教 (30571137)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 胃がん / オルガノイド / 胃癌

Outline of Final Research Achievements

In this study, we constructed a stomach tumor organoid library using organoid culture technology, and compare its phenotype with each result of molecular genetic analyses. Transformation of its morphology and niche requirement were caused by various genome and epigenomic changes, and it was found that CDH1 and TP53 co-mutations caused autonomous growth in gastric cancer, CDH1 and TP53 mutations cause autonomous growth. For verification, we established CDH1/TP53 co-mutated engineered gastric organoids. The engineered organoids could grow autonomously. Furthermore, we imploved the efficiency of the success rate of xeno-transplantation of gastric cancer organoids to immuno-deficient mice by co-transplantation with fibroblasts.
It can be expected to lead to a new treatment for gastric cancer.

Academic Significance and Societal Importance of the Research Achievements

本研究で構築した胃がんオルガノイドライブラリーは、これまでのin vitro研究で主に使用されてきた細胞株に比して、より臨床胃がんに近い特性を持ち、そのためがん研究の非常に有用なツールとなりうる。
また、本研究で用いられた、ヒト胃がんオルガノイドを培養上の形質で分類し、それぞれの分類において見出した分子遺伝学的特性を正常上皮に再現し検証した方法は、これまでにない新規の研究手法であり、他のがん腫や消化器疾患の研究進捗に非常に有用であると考えられる。

Research Products

• [Journal Article] Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis (2018)
  • Author(s): Nanki Kosaku、Toshimitsu Kohta、Takano Ai、Fujii Masayuki、Takahashi Sirirat、Sukawa Yasutaka、Ishida Hiroki、Sugimoto Shinya、Kawakubo Hirofumi、Kim Jihoon、Kitagawa Yuko、Sekine Shigeki、Koo Bon-Kyoung、Kanai Takanori、Sato Toshiro
  • Journal Title: Cell Volume: 174 Issue: 4 Pages: 856-869
  • DOI: 10.1016/j.cell.2018.07.027
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reconstruction of the Human Colon Epithelium In Vivo. (2018)
  • Author(s): Sugimoto S, Ohta Y, Fujii M, Matano M, Shimokawa M, Nanki K, Date S, Nishikori S, Nakazato Y, Nakamura T, Kanai T, Sato T.
  • Journal Title: Cell Stem Cell. Volume: 22 Issue: 2 Pages: 171-176
  • DOI: 10.1016/j.stem.2017.11.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression. (2018)
  • Author(s): Seino T, Kawasaki S, Shimokawa M, Tamagawa H, Toshimitsu K, Fujii M, Ohta Y, Matano M, Nanki K, Kawasaki K, Takahashi S, Sugimoto S, Iwasaki E, Takagi J, Itoi T, Kitago M, Kitagawa Y, Kanai T, Sato T.
  • Journal Title: Cell Stem Cell. Volume: 22 Issue: 3 Pages: 454-467
  • DOI: 10.1016/j.stem.2017.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] オルガノイドによる胃がんニッチ非依存性獲得機構の解明 (2019)
  • Author(s): 南木康作、佐藤俊朗、金井隆典
  • Organizer: 第105回日本消化器病学会総会