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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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2021: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2020: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
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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 / FOXO3a / リゾホスフォリパーゼD / リポクオリティ / リゾリン脂質代謝 / Foxo3a / がん幹細胞 / CML / オルガノイド |
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| Outline of Research at the Start |
がん幹細胞は非常に多くのがん細胞を産生する能力と抗がん剤治療に対する抵抗性を有しており、治療後に残存したがん幹細胞は再発や転移の原因となる．本研究では，慢性骨髄性白血病(CML)のマウスモデルを用いて，CMLのがん幹細胞(CML幹細胞)の抗がん剤抵抗性の制御における脂質代謝の役割の解明を目的とした研究を行なう．さらに，ヒト胃・大腸がん幹細胞を含む患者由来オルガノイド細胞を用いて脂質代謝の役割を解析し，CMLと上皮性腫瘍のがん幹細胞の間での脂質代謝の共通性を手掛りにヒトがん幹細胞の薬剤耐性機構の解明を目指す．
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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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| 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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Report
(4 results)
Research Products
(33 results)
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[Journal Article] Generation of Philadelphia chromosome in human leukemia by DNA breaks on the BCR and ABL1 genes using CRISPR/Cas9 system.2023
Author(s)
Tamai M, Fujisawa S, Nguyen Thao TT, Komatsu C, Kagami K, Kamimoto K, Omachi K, Kasai S, Harama D, Watanabe A, Akahane K, Goi K, Naka K, Kaname T, Teshima T, and Inukai T
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Journal Title
Cancer Gene Therapy
Volume: 30
Issue: 1
Pages: 38-50
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Statins Enhance the Molecular Response in Chronic Myeloid Leukemia when Combined with Tyrosine Kinase Inhibitors2021
Author(s)
Jang H-J*, Woo YM*, Naka K*(*contributed equally ), Park J-H, Han H-J, Kim H-J, Kim S-H, Ahn JS, KimTH, Kimura S, Zarabi S, Lipton JH, Minden MD, Jung CW, Kim H-J, Kim J-W, Kim DDH.
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Journal Title
Cancers
Volume: 13
Issue: 21
Pages: 5543-5543
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] KHDRBS3 promotes multi-drug resistance and anchorage-independent growth in colorectal cancer.2021
Author(s)
Ukai S, Sakamoto N, Taniyama D, Harada K, Honma R, Maruyama R, Naka K, Hinoi T, Takakura Y, Shimizu W, Ohdan H, Yasui W
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Journal Title
Cancer Sci
Volume: 112
Issue: 3
Pages: 1196-1208
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The lysophospholipase D enzyme Gdpd3 is required to maintain chronic myelogenous leukaemia stem cells.2020
Author(s)
Naka K, Ochiai R, Matsubara E, Kondo C, Yang KM, Hoshii T, Araki M, Araki K, Sotomaru Y, Sasaki K, Mitani K, Kim D-W, Ooshima A, Kim SJ.
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Journal Title
Nature Comm
Volume: 11
Issue: 1
Pages: 4681-4681
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of features of cancer stem cell2020
Author(s)
Ukai S, Honma R, Sakamoto N, Yamamoto Y, Pham QT, Harada K, Takashima T, Taniyama D, Asai R, Fukada K, Naka K, Tanabe K, Ohdan K, Yasui W
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Journal Title
Oncogene
Volume: 39
Issue: 50
Pages: 7265-7278
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] UC-63+ contributes to gastric cancer progression through regulation of NF-κB signaling2020
Author(s)
Sakamoto N, Sekino Y, Fukada, Pham QT, Honma R, Taniyama D, Ukai S, Takashima T, Hattori T, Naka K, Tanabe K, Ohdan H, Yasui W
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Journal Title
Gastric Cancer
Volume: 23
Issue: 5
Pages: 863-873
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Establishment and molecular biological analysis of 5-FU resistant gastric cancer organoids2020
Author(s)
Shoichi Ukai, Naoya Sakamoto, Ririno Honma, Daiki Taniyama, Quoc Thang Pham, Tsuyoshi Takashima, Kenji Harada, Kazuhito Naka, Kazuaki Tanabe, Hideki Ohdan, Wataru Yasui
Organizer
第79回日本癌学会学術総会
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