Investigation of epigenetic modifications that specify tissue identity of adult epithelial cells

• Project/Area Number: 18H02639
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Kyoto University
• Principal Investigator: Miyoshi Hiroyuki 京都大学, 医学研究科, 准教授 (30362479)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: エピジェネティクス / スフェロイド培養 / 組織幹細胞 / 癌幹細胞 / スフェロイド / がん幹細胞 / Wnt

Outline of Final Research Achievements

In this study, we investigated molecular and genetic mechanisms in which tissue and cancer stem cells specify their identity. Using a stem cell spheroid culture system, we demonstrated that transcriptional and epigenetic landscapes of normal tissue stem cells recapitulated their developmental stages. In colorectal cancer cells with low Wnt/beta-catenin signaling, cell growth and stemness were promoted partly by constitutive expression of MYC.

Academic Significance and Societal Importance of the Research Achievements

本研究で様々な組織から分離した上皮幹細胞を横断的に比較解析することにより、転写因子の組み合わせと強固なエピジェネティック修飾によって厳格に規定された臓器特異性の理解が進んだ。また、組織幹細胞の自家移植による組織修復の可能性が示された。
本研究で樹立した患者由来大腸がんスフェロイドは治療法開発のための有用な材料である。これらの培養でがん幹細胞が維持されるメカニズムを解明することにより、幹細胞性をターゲットとした治療戦略の開発が期待できる。

Research Products

• [Journal Article] Efficacious Combination Drug Treatment for Colorectal Cancer that Overcomes Resistance to KRAS G12C Inhibitors (2023)
  • Author(s): Matsubara Hiroyuki、Miyoshi Hiroyuki、Kakizaki Fumihiko、Morimoto Tomonori、Kawada Kenji、Yamamoto Takehito、Obama Kazutaka、Sakai Yoshiharu、Taketo Makoto Mark
  • Journal Title: Molecular Cancer Therapeutics Volume: 22 Issue: 4 Pages: 529-538
  • DOI: 10.1158/1535-7163.mct-22-0411
  • Peer Reviewed / Open Access
• [Journal Article] Novel and efficient method for culturing patient‐derived gastric cancer stem cells (2023)
  • Author(s): Morimoto Tomonori、Takemura Yukitoshi、Miura Takemitsu、Yamamoto Takehito、Kakizaki Fumihiko、An Hideo、Maekawa Hisatsugu、Yamaura Tadayoshi、Kawada Kenji、Sakai Yoshiharu、Yuba Yoshiaki、Terajima Hiroaki、Obama Kazutaka、Taketo Makoto Mark、Miyoshi Hiroyuki
  • Journal Title: Cancer Science Volume: 114 Issue: 8 Pages: 3259-3269
  • DOI: 10.1111/cas.15840
  • Peer Reviewed / Open Access
• [Journal Article] Chemosensitivity of Patient-Derived Cancer Stem Cells Identifies Colorectal Cancer Patients with Potential Benefit from FGFR Inhibitor Therapy (2020)
  • Author(s): Yamamoto Takehito、Miyoshi Hiroyuki、Kakizaki Fumihiko、Maekawa Hisatsugu、Yamaura Tadayoshi、Morimoto Tomonori、Katayama Toshiro、Kawada Kenji、Sakai Yoshiharu、Taketo M. Mark
  • Journal Title: Cancers Volume: 12 Issue: 8 Pages: 2010-2010
  • DOI: 10.3390/cancers12082010
  • NAID: 120006888015
  • Peer Reviewed / Open Access
• [Presentation] Development of personalized therapies using patient-derived gastrointestinal epithelial stem cells (2023)
  • Author(s): Hiroyuki Miyoshi
  • Organizer: The 100th Anniversary Annual Meeting of The Physiological Society of Japan, Kyoto, Japan.
• [Presentation] 高効率で低コストの患者由来大腸がんスフェロイド培養法 (2018)
  • Author(s): 三好 弘之
  • Organizer: 日本癌学会総会
• [Remarks] 京都大学医学部附属病院先端医療研究開発機構 大腸がん新個別化治療プロジェクト
  • URL: https://www4.mfour.med.kyoto-u.ac.jp/indexjp.html
• [Remarks] 京都大学医学部附属病院臨床研究総合センター（iACT) 大腸がん新個別化治療プロジェクト
  • URL: https://www4.mfour.med.kyoto-u.ac.jp/researchjp.html
• [Remarks] 京都大学医学研究科遺伝薬理学ユニット 研究内容
  • URL: http://www4.mfour.med.kyoto-u.ac.jp/researchjp.html
• [Patent(Industrial Property Rights)] 大腸がん患者の予後予測方法 (2024)
  • Inventor(s): 武藤誠、柿崎文彦、三好弘之、河田健二、小濵和貴
  • Industrial Property Rights Holder: 京都大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2024-017258
  • Filing Date: 2024