2022 Fiscal Year Final Research Report
Role of lysophospholipid metabolism enzyme Gdpd3 in regulating lipoquality in cancer stem cells
| Project/Area Number |
20H03517
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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 | Hiroshima University |
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Principal Investigator |
Kazuhito Naka 広島大学, 原爆放射線医科学研究所, 准教授 (70372688)
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| Co-Investigator(Kenkyū-buntansha) |
坂本 直也 国立研究開発法人国立がん研究センター, 先端医療開発センター, ユニット長 (20571798)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | CML幹細胞 / リゾリン脂質 / リゾフォスフォリパーゼD / Gdpd3 / TKI抵抗性 / 再発 / FOXO / beta-catenin |
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| Outline of Final Research Achievements |
Although recent advance on lipidomics technology made it possible to quantitatively measure lipid components, little is known about biological role for how cancer cells govern lipid metabolisms. Here, we found that Gdpd3 gene encoding a lysophospholipase D enzyme was highly expressed in murine chronic myelogenous leukemia (CML) stem cells than hematopoietic stem cells, and that Gdpd3-deficient CML stem cells significantly decreased the disease-relapsing capacity in the transplanted animal in vivo. We found that the Gdpd3-deficiency decreased in the levels of certain lipid mediators in CML bone marrow cells by sophisticated lipidomics analysis, indicating that the lysophospholipid metabolism resulted in producing the lipid mediators. Our results firstly demonstrate that Gdpd3-mediated lysophospholipid metabolic pathway is responsible for the maintenance of CML stem cells, and thus point toward a new biological significance of lysophospholipid biosynthesis for cancer recurrence in vivo.
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| Free Research Field |
腫瘍生物学
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| Academic Significance and Societal Importance of the Research Achievements |
慢性骨髄性白血病 (CML) 患者の治療はチロシンキナーゼ阻害薬 (TKI)の開発によって飛躍的な改善を遂げた．しかし, TKI治療だけでCMLは根治せず，TKI抵抗性の再発がおこることが重大な課題となっている． CML幹細胞はこのような再発の原因となることが知られている．本研究では，CML幹細胞の自己複製能の維持，及びTKI抵抗性にリゾリン脂質代謝酵素Gdpd3が重要な役割を担うことを解明した．従って，Gdpd3によるリゾリン脂質代謝はCML幹細胞の再発を克服するための新しい治療標的となることが期待される．
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