Generation of artificial colorectal cancer by gene network perturbation

• Project/Area Number: 16K09325
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: Matano Mami 慶應義塾大学, 医学部(信濃町), 研究員 (20439889)
• Co-Investigator(Kenkyū-buntansha): 佐藤 俊朗 慶應義塾大学, 医学部(信濃町), 教授 (70365245)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 大腸癌 / オルガノイド / 大腸がん / 癌

Outline of Final Research Achievements

The factors contributing in the malignant transformation process of normal colon epithelium are still unknown. The genetically-engineered normal colon organoids in our laboratory did not develop into a colorectal cancer, suggesting the involvement of additional factors. We assumed the involvement of the epigenetic changes and aimed to identify the transcription factors. To identify the transcription factors, we extracted the transcription factors using our database of colorectal cancer organoids, and constructed the overexpression vectors. We introduced them into genetically-engineered normal colon organoids and transplanted to mice to evaluate the presence of liver metastasis. Consequently, no liver metastasis were observed with any combination of transcription factors, and we concluded that further study is required.

Academic Significance and Societal Importance of the Research Achievements

本研究結果の学術的意義は, 今回我々が選択した転写因子だけでは既存の大腸発癌の理論を補完・再現するには不十分である可能性が示唆されたことである. 本成果より, 今回着目した転写因子の変動をきたす, より根源的原因の探索の必要性が考えられた. 社会的意義として, その根源的原因が今後の治療標的となる可能性が示唆された.

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] Human Intestinal Organoids Maintain Self-Renewal Capacity and Cellular Diversity in Niche-Inspired Culture Condition (2018)
  • Author(s): Fujii Masayuki、Matano Mami、Toshimitsu Kohta、Takano Ai、Mikami Yohei、Nishikori Shingo、Sugimoto Shinya、Sato Toshiro
  • Journal Title: Cell Stem Cell Volume: 23 Issue: 6 Pages: 787-793
  • DOI: 10.1016/j.stem.2018.11.016
  • 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
• [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] Visualization and Targeting of LGR5+ Human Colon Cancer Stem Cells (2017)
  • Author(s): Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M, Date S, Sugimoto S, Kanai T, Sato T
  • Journal Title: Nature Volume: 印刷中 Issue: 7653 Pages: 13-14
  • DOI: 10.1038/nature22081
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements. (2016)
  • Author(s): Fujii M, Shimokawa M, Date S, Takano A, Matano M, Ohta Y, Nanki K, Kawasaki K, Nakazato Y, Uraoka T, Watanabe T, Kanai T, Sato T.
  • Journal Title: Cell Stem Cell Volume: 18 Issue: 6 Pages: 827-838
  • DOI: 10.1016/j.stem.2016.04.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Active and water-soluble form of lipidated Wnt protein is maintained by a serum glycoprotein afamin/α-albumin. (2016)
  • Author(s): Mihara, E., Hirai, H., Yamamoto, H., Tamura-Kawakami, K., Matano, M., Kikuchi, A., Sato, T., and Takagi, J.
  • Journal Title: Elife Volume: 5 Pages: 1-19
  • DOI: 10.7554/elife.11621
  • Peer Reviewed / Open Access