Metabolic hallmark of epithelial-mesenchymal transition in non-small cell lung cancer

• Project/Area Number: 16K21361
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology; Pathological medical chemistry
• Research Institution: Keio University
• Principal Investigator: TABATA Sho 慶應義塾大学, 政策・メディア研究科(藤沢), 訪問講師 (30708342)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: がん代謝 / 上皮間葉転換 / EMT / metabolome / メタボローム

Outline of Final Research Achievements

Epithelial-mesenchymal transition (EMT) is a key event in cancer metastasis that directly contributes to poor prognosis. Here, we found that the loss of amino acids elicited by TGF-β signaling are important for transdifferentiation and consequently contribute to metastasis and anti-cancer drug resistance. These findings suggest that the loss of amino acids induced by TGF-β is critical for EMT in cancer cells, and indicate a potential target for therapeutics.

Academic Significance and Societal Importance of the Research Achievements

これまでのEMT研究では、EMTに関連する遺伝子の転写、翻訳機構、非コードRNAの制御、選択的スプライシングやタンパク質安定性など、様々な分子機構が報告されている。しかしながら、EMT特異的な代謝変化およびその機構については十分な理解がなされていない。今回、EMTにおける網羅的な代謝解析を行い、特異的アミノ酸代謝を見出し、その代謝を制御する代謝遺伝子を同定した。本結果は、がんEMTの理解を深めることができ、がん治療の開発に繋がる可能性がある。

Research Products

• [Int'l Joint Research] シンシナティ大学/Dep. of Internal Medicine/佐々木研究室(米国)
• [Journal Article] Thymidine catabolism promotes NADPH oxidase-derived reactive oxygen species (ROS) signalling in KB and yumoto cells (2018)
  • Author(s): Tabata S, Yamamoto M, Goto H, Hirayama A, Ohishi M, Kuramoto T, Mitsuhashi A, Ikeda R, Haraguchi M, Kawahara K, Shinsato Y, Minami K, Saijo A, Toyoda Y, Hanibuchi M, Nishioka Y, Sone S, Esumi H, Tomita M, Soga T, Furukawa T, Akiyama SI.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 6760-6760
  • DOI: 10.1038/s41598-018-25189-y
  • NAID: 120006875668
  • Peer Reviewed / Open Access
• [Journal Article] Beta-galactosidase-responsive synthetic biomarker for targeted tumor detection. (2018)
  • Author(s): Nishihara T, Kuno S, Nonaka H, Tabata S, Saito N, Fukuda S, Tomita M, Sando S, Soga T.
  • Journal Title: Chem Commun (Camb) Volume: 54 Issue: 83 Pages: 11745-11748
  • DOI: 10.1039/c8cc06068a
  • Peer Reviewed
• [Journal Article] Development of a sheathless CE-ESI-MS interface (2018)
  • Author(s): Hirayama A, Abe H, Yamaguchi N, Tabata S, Tomita M, Soga T.
  • Journal Title: ELECTROPHORESIS Volume: 印刷中 Issue: 11 Pages: 1382-1389
  • DOI: 10.1002/elps.201800017
  • Peer Reviewed
• [Journal Article] Thymidine phosphorylase in cancer aggressiveness and chemoresistance (2018)
  • Author(s): Furukawa T, Tabata S, Yamamoto M, Kawahara K, Shinsato Y, Minami K, Shimokawa M, Akiyama SI.
  • Journal Title: Pharmacological Research Volume: 28 Pages: 15-20
  • DOI: 10.1016/j.phrs.2018.03.019
  • Peer Reviewed / Open Access
• [Journal Article] Thymidine Catabolism as a Metabolic Strategy for Cancer Survival (2017)
  • Author(s): Tabata S, Yamamoto M, Goto H, Hirayama A, Ohishi M, Kuramoto T, Mitsuhashi A, Ikeda R, Haraguchi M, Kawahara K, Shinsato Y, Minami K, Saijo A, Hanibuchi M, Nishioka Y, Sone S, Esumi H, Tomita M, Soga T, Furukawa T, Akiyama SI
  • Journal Title: Cell Rep Volume: 19 Issue: 7 Pages: 1313-1321
  • DOI: 10.1016/j.celrep.2017.04.061
  • NAID: 120007001420
  • Peer Reviewed / Open Access
• [Journal Article] Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC (2017)
  • Author(s): Satoh K, Yachida S, Sugimoto M, Oshima M, Nakagawa T, Akamoto S, Tabata S, Saitoh K, Kato K, Sato S, Igarashi K, Aizawa Y, Kajino-Sakamoto R, Kojima Y, Fujishita T, Enomoto A, Hirayama A, Ishikawa T, Taketo MM, Kushida Y, Haba R, Okano K, Tomita M, Suzuki Y, Fukuda S, Aoki M, Soga T.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 114 Issue: 37
  • DOI: 10.1073/pnas.1710366114
  • Peer Reviewed
• [Journal Article] Synthetic Biomarker Design Using Analyte-Responsive Acetaminophen (2017)
  • Author(s): Nishihara, T. Inoue, J. Tabata, S. Murakami, S. Ishikawa, T. Saito, N. Fukuda, S. Tomita, M. Soga, T.
  • Journal Title: Chembiochem Volume: in press Issue: 10 Pages: 1-5
  • DOI: 10.1002/cbic.201700023
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mitochondrial Mg2+ homeostasis decides cellular energy metabolism and vulnerability to stress (2016)
  • Author(s): Yamanaka R, Tabata S, Shindo Y, Hotta K, Suzuki K, Soga T, Oka K
  • Journal Title: Scientific Reports Volume: 6-30027 Issue: 1 Pages: 30027-30027
  • DOI: 10.1038/srep30027
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] オンコメタボライトL-2HGによる新規がん生存シグナル (2018)
  • Author(s): 田畑祥、曽我朋義
  • Organizer: 第6回がんと代謝研究会
  • Invited
• [Presentation] 多層オミックス解析による肺がん上皮間葉転換における新規代謝機構の探索 (2018)
  • Author(s): 中宿 文絵、田畑 祥、坂本 毅治、平山 明由、山田 忠明、衣斐 寛倫、矢野 聖二、冨田 勝、曽我 朋義
  • Organizer: 第6回がんと代謝研究会
• [Presentation] Metabolic Hallmark of TGF-β-induced Epithelial Mesenchymal Transition in Non-Small Cell Lung Cancer (2016)
  • Author(s): Fumie Nakasuka, Sho Tabata, Tadaaki Yamada, Goto Hisatsugu, Seiji Yano, Yasuhiko Nishioka, Tomoyoshi Soga, Masaru Tomita
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Thymidine異化代謝による新規エネルギー産生機構 (2016)
  • Author(s): 田畑祥、山本雅達、後東久嗣、平山明由、西岡安彦、江角浩安、冨田 勝、曽我朋義、古川龍彦、秋山伸一
  • Organizer: 第4回がんと代謝研究会
  • Place of Presentation: かごしま県民交流センター（鹿児島県鹿児島市）
  • Year and Date: 2016-07-07
  • Invited
• [Book] がん代謝 ワールブルグを超えて全容解明に挑む（項：チミジン異化代謝） (2017)
  • Author(s): 田畑 祥、古川 龍彦、秋山 伸一
  • Total Pages: 6
  • Publisher: 羊土社
  • ISBN: 9784758103633