Tolerance of cancer cells against amino acids deprivation in tumor microenvironments
| Project/Area Number |
19H03496
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Tsuyoshi Osawa 東京大学, 先端科学技術研究センター, 准教授 (50567592)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2022: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
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| Keywords | がん微小環境 / アミノ酸 / がん代謝 / 転写・代謝制御 |
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| Outline of Research at the Start |
腫瘍微小環境はがんの増殖・転移・浸潤・薬剤耐性などの悪性化に重要な役割を果たす。本研究は、腫瘍微小環境におけるアミノ酸代謝適応機構の解明を目的とし、腫瘍微小環境における（１）アミノ酸欠乏感知機構の解明、（２）アミノ酸欠乏に対する細胞適応機構の解析、（３）低酸素・低栄養・低pHのストレス適応とアミノ酸代謝のクロストークの解明、及び、（４）現存する化学療法との併用における相乗効果の検討、について検討する。本研究から低栄養で悪性化するがん細胞を攻略する画期的ながん治療法の開発や、難治性疾患である先天性アミノ酸代謝異常疾患の病態生理解明や治療法開発にも応用可能である。
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| Outline of Final Research Achievements |
The tumor microenvironment plays an important role in canecr malignancy, such as metastasis, invasion, and drug resistance. Cancer cells in the extreme tumor microenvironment of hypoxia, nutrition deprivation and acidic pH contribute to cancer malignancy through the glycolysis, acetate metabolism, and glutamine metabolic adaptations through transcriptional regulation of HIF1α, ATF4, and SREBP2. This study aimed to elucidate the mechanisms of adaptation to amino acid metabolism in tumor microenvironment, including elucidation of (1) sensor for amino acid deficiency, (2) adaptive mechanism to amino acid deficiency of cancer cells, (3) cross-talk between stress adaptation to hypoxia, nutrient deprivation and acidic pH through amino acid metabolism and found a novel adaptive mechanism for amino acid deprivation.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究における、アミノ酸欠乏・適応機構の解析から、ｍTOR非依存的なアミノ酸適応機構を同定しつつあり、さらに、オルガネラレベルでの解析から、ミトコンドリアや小胞体が１アミノ酸の欠乏でダイナミックに変動することを見出している。現在、オルガネラ動態と単１細胞の遺伝子発現をリンクさせ、アミノ酸感知・適応機構を引き続き検討している。また、環境ストレス適応とアミノ酸代謝のクロストークの解明から、ストレス適応と協調的に働く、mTOR複合体を介さない新たなストレスシグナル経路を見出した。このようにアミノ酸欠乏・適応機構の解明は、将来的にがんや生活習慣病の画期的な治療標的となることが期待できる。
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Report
(5 results)
Research Products
(48 results)
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[Journal Article] Metagenomic identification of microbial signatures predicting pancreatic cancer from a multinational study2022
Author(s)
Nagata N, Nishijima S, Kojima Y, Hisada Y, Imbe K, Miyoshi-Akiyama T, Suda W, Kimura M, Aoki R, Sekine K, Ohsugi M, Miki K, Osawa T, Ueki T, Oka S, Mizokami M, Kartal E, Schmidt TSB, Molina-Montes E, Estudillo L, Malats N, Trebicka J, Kersting S, Langheinrich M, Bork P, Uemura N, Itoi T, and Kawai T
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Journal Title
Gastroenterology
Volume: 163
Issue: 1
Pages: 222-238
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis2022
Author(s)
Murakami K, Sasaki Y, Asahiyama M, Yano W, Takizawa T, Kamiya W, Matsumura Y, Anai M, Osawa T, Fruchart JC, Fruchart-Najib J, Aburatani H, Sakai J, Kodama T, Tanaka T.
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Journal Title
Cells
Volume: 11
Issue: 4
Pages: 720-720
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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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, Kajimura S.
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Journal Title
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma.2021
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 Sci.
Volume: 112
Issue: 7
Pages: 2855-2869
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content.2020
Author(s)
Sasaki Y, Asahiyama M, Tanaka T, Yamamoto S, Murakami K, Kamiya W, Matsumura Y, Osawa T, Anai M, Fruchart JC, Aburatani H, Sakai J, Kodama T.
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Journal Title
Sci Rep
Volume: 10
Issue: 1
Pages: 7817-7817
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT22019
Author(s)
Osawa T, Shimamura T, Saito K, Hasegawa Y, Ishii N, Nishida M, Ando R, Kondo A, Anwar M, Kato K, Endo K, Yamano S, Kanki Y, Matsumura Y, Minami T, Tanaka T, Anai M, Wada Y, Wanibuchi H, Hayashi M, Hamada A, Yoshida M, Yachida S, Nakao M, Sakai J, Aburatani H, Shibuya M, Hanada K, Miyano S, Soga T, Kodama T
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Journal Title
Cell Rep.
Volume: 29(1)
Issue: 1
Pages: 89-103
DOI
Related Report
Peer Reviewed / Open Access
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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
Related Report
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