Elucidation of renal tumorigenesis under FLCN deficiency
| Project/Area Number |
19K09694
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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 56030:Urology-related
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| Research Institution | Yokohama City University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
矢尾 正祐 横浜市立大学, 医学研究科, 客員教授 (00260787)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 遺伝性腎癌 / BHD症候群 / シングルセル発現解析 / がん微小環境 / 免疫チェックポイント阻害剤 / 腫瘍内不均一性 / FLCN / FLCN/FNIP1/FNIP2複合体 / 細胞内輸送 / エピゲノム |
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| Outline of Research at the Start |
家族性腎癌症候群、Birt-Hogg-Dube; (BHD)症候群の原因遺伝子として同定されたfolliculin (FLCN)は、腎臓細胞の増殖を直接制御する重要な腎癌抑制遺伝子ですが、FLCNの膜輸送における生理的意義はとても議論のあるところとなっております。そこで本研究では、哺乳動物に存在するRab GTPアーゼとFLCNの関連を網羅的に調べ、膜輸送や腎臓細胞増殖における生理的意義を検証します。以上により、FLCN欠失下の腎癌発生機序が明らかとなり、新規腎癌治療薬の開発基盤が確立されます。
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| Outline of Final Research Achievements |
We have identified novel FLNC ineracting partners and are investigating physiological meaning of those interactions using animal models. Furthermore, we have conducted single cell RNA-seq of BHD-associated kidney cancer and found that BHD-associated kidney cancer exhibits molecular proflinig simlimar to that of intercalating cell of collecting duct, transcriptomic intratumor heterogeneity (tITH) and differentially expressed genes including SLC4A4, HERC1, PLAAT4 and MIF. We also revealed distinct tumor microenvironment which is unique to each hereditary kidney cancer. These findings provides mechanistic insights into renal tumorigenesis as well as an oppotunity to develop novel therapeutics and diagnostics to hereditary nad sporadic kidney cancers.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、FLCNの膜輸送における役割が解明され、今後、膜輸送という全く新しい経路を標的とした新規腎癌治療薬の開発が期待できます。さらに今回のシングルセル発現解析により、詳細な腎腫瘍化機構の解明がなされただけでなく、免疫環境を含めたがん微小環境が明らかとなりました。これらの発見は腎癌細胞に対する新規治療薬開発ならびに免疫チェックポイント阻害剤や血管新生阻害剤などの腎癌の標準薬物療法の精密化につながります。
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Report
(4 results)
Research Products
(17 results)
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[Journal Article] Diagnostic Impacts of Clinical Laboratory Based p2PSA Indexes on any Grade, Gleason Grade Group 2 or Greater, or 3 or Greater Prostate Cancer and Prostate Specific Antigen below 10 ng/ml.2020
Author(s)
Ito K, Yokomizo A, Tokunaga S, Arai G, Sugimoto M, Akakura K, Hasumi H, Sakai H, Ouraji A, Oki R, Kashiwagi E, Kobori Y, Hirama H, Kitoh H, Uemura H, Hakariya T, Suzuki K
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Journal Title
J Urol.
Volume: 203
Issue: 1
Pages: 83-91
DOI
Related Report
Peer Reviewed
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[Journal Article] TFE3 Xp11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease.2019
Author(s)
Baba M, Furuya M, Motoshima T, Lang M, Funasaki S, Ma W, Sun HW, Hasumi H, Huang Y, Kato I, Kadomatsu T, Satou Y, Morris N, Karim BO, Ileva L, Kalen JD, Wilan Krisna LA, Hasumi Y, Sugiyama A, Kurahashi R, Nishimoto K, Oyama M, Nagashima Y, Kuroda N, Araki K, Eto M, Yao M, Kamba T, Suda T, Oike Y, Schmidt LS, Linehan WM
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Journal Title
Molecular Cancer Research
Volume: 印刷中
Issue: 8
Pages: 1613-1626
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Early assessment with 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography to predict short-term outcome in clear cell renal carcinoma treated with nivolumab2019
Author(s)
Tabei T, Nakaigawa N, Kaneta T, Ikeda I, Kondo K, Makiyama K, Hasumi H, Hayashi N, Kawahara T, Izumi K, Osaka K, Muraoka K, Teranishi JI, Miyoshi Y, Yumura Y, Uemura H, Kobayashi K, Inoue T, Yao M.
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Journal Title
BMC Cancer
Volume: 19
Issue: 1
Pages: 298-298
DOI
Related Report
Peer Reviewed / Open Access
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