cellular diversity in mammalian intestinela tissue

2021 Fiscal Year Final Research Report

• Project Area: Integrated analysis and regulation of cellular diversity
• Project/Area Number: 17H06333
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: YAO Ryoji 公益財団法人がん研究会, がん研究所 細胞生物部, 部長 (80291095)
• Project Period (FY): 2017-06-30 – 2022-03-31
• Keywords: 消化管組織 / がんモデルマウス / オルガノイド

Outline of Final Research Achievements

To elucidate the cellular diversity in intestinal tissue and their alteration induced by driver mutations found in human colorectal cancers, we established a series of conditional knockout mice and their organoids. Single cell expression analysis of organoids followed by informatics analyses suggested the cellular diversity in norma intestine and their alterations by the driver mutations. Notably, they alters not only cellular diversity in intestinal epithelial cells, but also affects stromal cells in their microenvironment. These alterations were histologically validated in mouse models. Overall, this study revealed the cellular heterogeniety of intestinal tissues in normal and mutant tissues,, and provide the clue to develop the treatment of intestinal tumor by targeting interaction between intestinal epithelia cells and microenvironment.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究開発では、哺乳動物の消化管組織の細胞多様性とがん化に伴う変化を明らかにした。その結果、ヒト大腸がんの発生に関与する遺伝子変異は、がん組織を変化させるのみでなく、周囲の微小環境にいる間質細胞にも影響することが明らかになった。これらの結果から、現在有効な分子標的薬がない、RAS変異陽性大腸がんに対して、がん組織と微小環境との相互作用を標的とする治療戦略を提唱することができた。