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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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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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 / 大腸がん抑制遺伝子 / CRISPR-Cas9 / モデルマウス / トランスポゾン / ドライバー遺伝子 / 薬剤抵抗性 / がん抑制遺伝子 / 薬剤耐性 / 治療抵抗性 / スクリーニング / 癌 / ゲノム / 遺伝子 / 遺伝学 / 動物 |
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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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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Report
(4 results)
Research Products
(17 results)
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[Journal Article] CRISPR-Cas9 mediated gene knockout in intestinal tumor organoids provides functional validation for colorectal cancer driver genes.2019
Author(s)
Takeda H, Kataoka S, Nakayama M, Ali MAE, Oshima H, Yamamoto D, Park JW, Takegami Y, An T, Jenkins NA, Copeland NG, and Oshima M.
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Journal Title
Proc Natl Acad Sci USA
Volume: 116
Issue: 31
Pages: 15635-15644
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia2017
Author(s)
1.Sarah P. Short, Jumpei Kondo, Whitney G. Smalley-Freed, Haruna Takeda, Michael R. Dohn, Anne E. Powell, Robert H. Carnahan, Mary K. Washington, Manish Tripathi, D. Michael Payne, Nancy A. Jenkins, Neal G. Copeland, Robert J. Coffey and Albert B. Reynolds
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Journal Title
J Clin Invest.
Volume: 127
Pages: 4462-4476
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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