Molecular mechanism of subtype shift underlying plasticity and therapy-resistance in glioblastoma
Project/Area Number |
20K07566
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 50010:Tumor biology-related
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Research Institution | Kanazawa University |
Principal Investigator |
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
|
Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
|
Keywords | グリオーマ / 膠芽腫 / 悪性脳腫瘍 |
Outline of Research at the Start |
悪性神経膠腫は治療抵抗性の予後不良悪性疾患であり、有効な治療法はまだない。原因の一つに、グリオーマ細胞の形質が不均一かつ可塑的であることが挙げられる。グリオーマは4つのサブタイプに分類され、様々なストレスにより腫瘍内においてサブタイプの転換が起こる。この機構の理解が、治療抵抗性獲得の解明の鍵になると期待されている。本研究では、患者由来グリオーマ細胞へのリポーター遺伝子導入法を駆使し、OLIG2の発現制御および機能解析を通して、細胞系譜転換と治療抵抗性獲得の間の分子機構の解明を目指す。本研究により、細胞系譜転換を抑制し、治療抵抗性を克服するための新たなアプローチの発見が期待される。
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Outline of Final Research Achievements |
Glioblastoma (GBM), the most aggressive type of brain tumor, is classified into some subtypes in which mesenchymal subtype GBM is therapy-resistant. Radiation and temozolomide are main therapeutics for GBM, however, recurrence occurs due to therapy-resistance through proneural-mesenchymal transition. The mechanisms of this subtype-shift and therapy-resistance in mesenchymal subtype have been unclear. To address these questions, we focused on a mesenchymal subtype and therapy-resistance marker, CD44. In this study, we found that hypoxia and OLIG2 suppressed CD44 levels and therapy-resistance. RNA-seq analysis showed lysosome-related genes were up-regulated in the CD44-high subpopulation. A lysosome inhibitor increased the sensitivity of CD44-high subpopulation to temozolomide and radiation.
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Academic Significance and Societal Importance of the Research Achievements |
膠芽腫(グリオブラストーマ)の細胞系譜転換のメカニズムを明らかにし、治療抵抗性に働く経路を特定した本研究成果をさらに発展させることによって、治療抵抗性腫瘍に対しても、これまでの治療法をより効果的に作用させる方法の開発につながるものと考えられる。
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Report
(4 results)
Research Products
(11 results)
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[Journal Article] RHEB is a potential therapeutic target in T cell acute lymphoblastic leukemia2022
Author(s)
Pham Loc Thi、Peng Hui、Ueno Masaya、Kohno Susumu、Kasada Atuso、Hosomichi Kazuyoshi、Sato Takehiro、Kurayoshi Kenta、Kobayashi Masahiko、Tadokoro Yuko、Kasahara Atsuko、Shoulkamy Mahmoud I.、Xiao Bo、Worley Paul F.、Takahashi Chiaki、Tajima Atsushi、Hirao Atsushi
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Journal Title
Biochemical and Biophysical Research Communications
Volume: 621
Pages: 74-79
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Pillar[6]arene acts as a biosensor for quantitative detection of a vitamin metabolite in crude biological samples2020
Author(s)
Masaya Ueno, Takuya Tomita, Hiroshi Arakawa, Takahiro Kakuta, Tada-aki Yamagishi, Jumpei Terakawa, Takiko Daikoku, Shin-ichi Horike, Sha Si, Kenta Kurayoshi, Chiaki Ito, Atsuko Kasahara, Yuko Tadokoro, Masahiko Kobayashi, Tsutomu Fukuwatari, Ikumi Tamai, Atsushi Hirao & Tomoki Ogoshi
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Journal Title
Communications Chemistry
Volume: 3
NAID
Related Report
Peer Reviewed / Open Access
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