The mechanistic analyses of modulation of Tumor microenvironment by characteristic metabolite released from NRF2-addicted cancer cells
| Project/Area Number |
19K07379
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 49010:Pathological biochemistry-related
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| Research Institution | Tohoku Medical and Pharmaceutical University (2021-2022)
Tohoku University (2019-2020) |
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Principal Investigator |
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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 |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 腫瘍免疫 / NRF2 / KEAP1 / 代謝物 / 肺がん / 代謝 / NRF2依存性がん / メタボローム / 腫瘍微小環境 |
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| Outline of Research at the Start |
本申請研究では、発がんモデルマウスや、マウス同種間で移植可能な悪性度の高いNRF2依存性がん細胞を構築し、転移モデル実験などに供することで、がん細胞が放出する特徴的な代謝物の腫瘍微小環境への影響を解析し、がん細胞の代謝物による腫瘍微小環境の改変（Metabolic instruction）ががんの悪性化に果たす役割を解明する。また、がん細胞の代謝が腫瘍微小環境のみならず、担がん宿主の全身状態にも影響する可能性を検証するために、担がんマウスの運動能などを長期的に観察する。
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| Outline of Final Research Achievements |
Transcription factor NRF2 is constitutively activated by somatic mutation of KEAP1 or NFE2L2 genes in lung cancer, conferring the resistance against chemotherapy and radiotherapy to cancer cells. In order to clarify the mechanisms how persistent NRF2 activation contributes to cancer malignancy, we test the hypothesis that NRF2-activated cancer cells contribute to cancer malignancy by releasing immunosuppressive metabolite. First, NRF2-activated model cancer cells which is transplantable to C57BL6 mice is successfully established to analyze the immunosuppressive feature of tumor microenvironment. In addition to the result, specific features of NRF2-activated lung cancer patients are analyzed by the public available dataset and was found that certain types of immuno were drastically changed.
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| Academic Significance and Societal Importance of the Research Achievements |
NRF2依存性がん細胞は悪性腫瘍をしばしば形成しており、腫瘍微小環境に中において免疫細胞やがん繊維芽細胞の機能を調節しているかといった事については現在までに実験学的には証明されていなかった。近年の解析では、免疫チェックポイント阻害剤などに対しても抵抗性を示していることがヒト肺がんデータベースより明らかになっている。本研究ではこれらのメカニズムについて有用な知見を提供することができる点で、難治がんであるNRF2活性化がんの新たな治療標的の開発に繋がる研究となることが予想され、関連分野に波及するそのインパクトや効果は大きいと考えられる。
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Report
(5 results)
Research Products
(28 results)
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[Journal Article] Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 directly binds and stabilizes Nrf2 in breast cancer.2022
Author(s)
Saeidi S, Kim SJ, Guillen-Quispe YN, Jagadeesh ASV, Han HJ, Kim SH, Zhong X, Piao JY, Kim SJ, Jeong J, Shin YJ, Cha YJ, Lee HB, Han W, Min SH, Tian W, Kitamura H, Surh YJ
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Journal Title
FASEB J
Volume: 36
Issue: 1
Pages: 1-16
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Autophagy regulates lipid metabolism through selective turnover of NCoR12019
Author(s)
Saito Tetsuya、Kuma Akiko、Sugiura Yuki、Ichimura Yoshinobu、Obata Miki、Kitamura Hiroshi、Okuda Shujiro、Lee Hyeon-Cheol、Ikeda Kazutaka、Kanegae Yumi、Saito Izumu、Auwerx Johan、Motohashi Hozumi、Suematsu Makoto、Soga Tomoyoshi、Yokomizo Takehiko、Waguri Satoshi、Mizushima Noboru、Komatsu Masaaki
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Journal Title
Nature Communications
Volume: 10
Issue: 1
Pages: 41467-41467
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Inhibition of xCT,cystine/glutamate transporter, supresses chronic inflammation in a mouse model of inflammatory bowel disease2022
Author(s)
岩城英也, 関根弘樹, 村上昌平, 加藤伸史, 北村大志, 福田真嗣, 曽我朋義, 角田 洋一, 正宗淳, 本橋ほづみ
Organizer
The 12th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
Related Report
Int'l Joint Research
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[Presentation] Enhancer remodeling at the NOTCH3 locus licenses NRF2 for the promotion of a stem-like phenotype in non-small cell lung cancers.2019
Author(s)
Keito Okazaki, Hayato Anzawa, Hiroshi Kitamura, Yoshiaki Onodera, Md. Morshedul Alam, Daisuke Matsumaru, Takuma Suzuki, Fumiki Katsuoka, Nao Ota, Akira Sakurada, Yoshinori Okada, Masayuki Yamamoto, Takashi Suzuki, Kengo Kinoshita, Hiroki Sekine, Hozumi Motohashi.
Organizer
The Environmental Response V
Related Report
Int'l Joint Research
