2020 Fiscal Year Final Research Report
Identification of colorectal cancer driver genes involved in cancer development and therapeutic resistance.
Project/Area Number |
17H03586
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Tumor biology
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Research Institution | National Cancer Center Japan (2019-2020) Kanazawa University (2017-2018) |
Principal Investigator |
Takeda Haruna 国立研究開発法人国立がん研究センター, 研究所, ユニット長 (80647975)
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Project Period (FY) |
2017-04-01 – 2021-03-31
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Keywords | 大腸がん / マウスモデル / がんドライバー遺伝子 / オルガノイド |
Outline of Final Research Achievements |
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. In our previous study, we performed genome-wide Sleeping Beauty transposon-based mutagenesis screening in mice and provided comprehensive datasets of candidate CRC driver genes. However, functional validation for most candidate CRC driver genes has not been performed. Here, we describe a platform for functionally validating CRC driver genes that utilizes CRISPR-Cas9 in mouse intestinal tumor organoids in xenograft models. We used genetically defined benign tumor-derived organoids carrying mutations in Apc and Kras. These studies showed that Acvr1b, Acvr2a and Arid2 could function as tumor suppressor genes in CRC. This experimental system can also be applied to mouse intestinal organoids carrying other sensitizing mutations as well as organoids derived from other organs, which could further contribute to identification of novel cancer driver genes and new drug targets.
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Free Research Field |
腫瘍生物学
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Academic Significance and Societal Importance of the Research Achievements |
本研究のオルガノイドを用いたがん化能検証実験系は、多くの組織に応用可能であり、急速に進むがんゲノム解読研究から明らかにされる多くの変異遺伝子が、がん形成に寄与する変異であるかを生体内で効率的に検証する方法として利用できる。今後のがん研究は、ゲノム解読によって同定された変異遺伝子の機能検証を行う方向に展開していくと考えられ、本研究で確立した方法が、がんの機序解明に大きく貢献できると考えられる。
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