2021 Fiscal Year Final Research Report
Development of therapeutic strategy targeting epithelial-mesenchymal transition and cell-fate determination factor for malignancy
| Project/Area Number |
18K07335
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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 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | Doshisha Women's College of Liberal Arts (2021)
Nagahama Institute of Bio-Science and Technology (2018-2020) |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Keywords | 上皮間葉転換 / 間葉転換解除 / 脂肪分化 / メタボローム / 上皮化誘導shRNA |
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| Outline of Final Research Achievements |
To develop a molecular-targeted therapy for epithelial-mesenchymal transition (EMT), which is urgently needed, we developed an original screening system to visualize EMT and obtained two epithelialization-inducing shRNAs. Lipid uptake and CD36 expression increased upon PPAR gamma activation only in H-Ras-transfected mammary mesenchymal cells, which showed high expression of CD73 and PPARγ. Lung cancer cells showed a marked increase in intracellular granules upon EMT and PPARγ stimulation. Metabolomic analysis showed activation of glycolytic pathway in mammary epithelial cells, suppression of lactate fermentation and activation of pentose phosphate pathway and sorbitol pathway by EMT. Oncogene-introduced mesenchymal cells with cancer stem cell properties were found to have both epithelial and mesenchymal metabolic features.
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| Free Research Field |
分子腫瘍学、薬物治療学
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| Academic Significance and Societal Importance of the Research Achievements |
間葉転換は由来臓器を超えて悪性腫瘍の治療抵抗性、不均一性の原因であるが、分子標的薬．免疫チェックポイント阻害薬が多数開発されてきた現在においても、間葉転換を標的にした治療は未だなく、喫緊の課題である。我々はこれまでの研究で、複数の有望な分子・経路・治療候補を同定してきている。これまでに、上皮化誘導shRNA、細胞運命制御決定因子の間葉転換への関与、脂肪分化誘導の可能性、間葉転換癌細胞に特徴的な代謝経路を見出してきた。さらに独自に開発したEMT/METレポーターを駆使し、上記のアプローチの有効性を検証することによって、未だ根治が達成できない、不均一な悪性腫瘍の根治をもたらす可能性がある。
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