Organoid-based modeling of gastric carcinogenesis and elucidation of its mechanism

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08019
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: Hippo Yoshitaka 千葉県がんセンター(研究所), 研究所, 研究所長 (30359632)
• Co-Investigator(Kenkyū-buntansha): 丸 喜明 千葉県がんセンター(研究所), 発がん研究グループ 発がん制御研究部, 研究員 (30742754)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 胃がん / オルガノイド / 発がん

Outline of Final Research Achievements

Tumors with diverse histology were generated by reconstituting genetic abnormalities that are frequently found in human gastric cancer in normal murine gastric organoids. We found high inter-tumor diversity and intratumor heterogeneity even with the same genetic aberrations, and that active Kras mutations alone are eliminated in culture. Epigenetic changes induced by stromal interactions in subcutaneous immunocompromised mice and the importance of clonal selection were confirmed. Genotoxic substances were found to induce enhanced adenocarcinoma when administered to organoids with low tumorigenicity. The results were partially replicated in genetically engineered mice, including the induction of signet-ring cells, a characteristic feature of diffuse-type gastric carcinoma.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

遺伝子改変マウスを作成しなくても、同等の胃発がんがオルガノイドを用いた皮下移植モデルによりかなりの程度迅速に再現可能であることを示した。ただし、腫瘍の多様性および腫瘍内不均一性が高いことから、上皮と遺伝子変異に加えて間質との局所的な相互作用の重要性が示唆された。化学発がんモデルも確立できたことから、化学発がんに抵抗性とされる胃がんの新規モデルとしての有用性が期待される。