Elucidation of amino acid adaptive sensor in cancer cells
| Project/Area Number |
19K22553
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 50:Oncology and related fields
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Osawa Tsuyoshi 東京大学, 先端科学技術研究センター, 特任准教授 (50567592)
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| Project Period (FY) |
2019-06-28 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
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| Keywords | 腫瘍微小環境 / がん代謝 / アミノ酸 / アミノ酸欠乏 / オミクス統合解析 / がん微小環境 / アミノ酸センサー / アミノ酸代謝 |
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| Outline of Research at the Start |
がんの転移・浸潤・薬剤耐性などの悪性化には腫瘍微小環境が重要な役割を果たす。本研究では、グルタミン欠乏を基軸としたがん細胞のアミノ酸欠乏のアダプティブセンサーの探索から新規がんの治療法の開発につながる研究を目的とする。本研究は、がん研究のみならず、アミノ酸代謝疾患研究、mTOR研究やオートファジー研究などの学術体系の変革や転換にも繋がる可能性を有し、アミノ酸代謝疾患の制御にも応用可能な研究である。
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| Outline of Final Research Achievements |
The tumor microenvironment plays an important role in malignant transformation such as growth, metastasis and drug resistance of cancer cells. The purpose of this study was to identify adaptive sensors to amino acid deficiency in cancer cells, inhibition of which can be utilized for the development of novel cancer treatments. We conducted researches on (1) exploration of adaptive sensors for amino acid deficiency and (2) elucidation of the adaptive mechanism of cancer to amino acid deficiency. We identified glutamine and other amino acid-specifically induced genes, histone modifications (H3K4me3, H3K27ac), promoters, enhancers, and possible upstream regulators. We identified candidate of sensors and regulators that are essential for amino acid deficiency, such as transcription factors and amino acid transporters.
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| Academic Significance and Societal Importance of the Research Achievements |
近年、がん細胞はロイシンなどの必須アミノ酸をmTOR複合体を介したシグナル伝達系で感知することが知られている。一方、グルタミンなどのアミノ酸欠乏感知機構は未だ不明な点が多い。本研究は、独自の低栄養培養やアミノ酸培養系を作成し、各アミノ酸で特異的に発現誘導される遺伝子群やエピゲノム制御機構を同定、各アミノ酸における上流転写因子を同定など、がん細胞の新規アミノ酸欠乏アダプティブ機構が存在する可能性を見出した。本研究により、がん悪性化を促進する新しいアミノ酸欠乏の感知・適応システムやアミノ酸代謝異常に関わる代謝経路や遺伝子変動の解明が可能となり、今後、新規がん治療法への応用が期待できる。
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Report
(3 results)
Research Products
(17 results)
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[Journal Article] Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever2021
Author(s)
Yoneshiro T, Kataoka N, Walejko JM, Ikeda K, Brown Z, Yoneshiro M, Crown SB, Osawa T, Sakai J, McGarrah RW, White PJ,Nakamura K, and Kajimura S
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Journal Title
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] TET1 upregulation drives cancer cell growth by aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma2021
Author(s)
Shirai K, Nagae G, Seki M, Kudo Y, Kamio A, Hayashi A, Okabe A, Ota S, Tsutsumi S, Fujita T, Yamamoto S, Nakaki R, Kanki Y, Osawa T, Midorikawa Y, Tateishi K, Ichinose M, Aburatani H
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Journal Title
Cancer Science
Volume: In press
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Peer Reviewed
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[Journal Article] Regnase-1-mediated post-transcriptional regulation is essential for hematopoietic stem and progenitor cell homeostasis2019
Author(s)
Kidoya H, Muramatsu F, Shimamura T, Jia W, Satoh T, Hayashi Y, Naito H, Kunisaki Y, Arai F, Seki M, Suzuki Y, Osawa T, Akira S., Takakura N.
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Journal Title
Nature Commun,
Volume: 10
Issue: 1
Pages: 1072-1072
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Book] 医学のあゆみ2019
Author(s)
多階層オミクス統合解析-オミクス解析
Total Pages
120
Publisher
医歯薬出版株式会社
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