Next-generation proteomics to reveal the mechanism for malignant transformation

• Project/Area Number: 17K19606
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: Kyushu University
• Principal Investigator: Masaki Matsumoto 九州大学, 生体防御医学研究所, 准教授 (60380531)
• Research Collaborator: Nakayama Keiichi
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: プロテオミクス / 代謝 / がん / がん代謝 / プロテオーム / 癌

Outline of Final Research Achievements

In this study, we established an in vitro model for malignant transformation from oncogene-induced pre-cancerous state cell line. In order to reveal the molecular basis of malignant transformation, the expression level of metabolic enzymes in these cell lines was quantified by our originally developed next-generation proteomics, iMPAQT. We found that glutamine metabolism is significantly altered during malignant transformation and PPAT which transfers nitrogen to 5-phosphoribosyl-1-pyrophosphate (PRPP), a precursor in nucleotide biosynthesis, from glutamine, acts as a key enzyme in cancer specific glutamine metabolism. We also demonstrated that attenuation of PPAT induces the reduction in the tumor size.

Academic Significance and Societal Importance of the Research Achievements

本研究によってがんの悪性進展過程においてグルタミン代謝経路が核酸合成に偏重してシフトしていることを見出した。このがん特有の代謝シフトの原因であるPPATの発現抑制によって腫瘍形成を減弱させることができたことから、この酵素が抗がん剤の有効なターゲットとなり得ることが示唆された。また、代謝酵素の一斉定量法を確立したことで、広範な疾患の分子機構を代謝経路の変化として捉えることが可能となった。

Research Products

• [Journal Article] The jPOST environment: an integrated proteomics data repository and database (2019)
  • Author(s): Moriya Yuki、Kawano Shin、Okuda Shujiro、Watanabe Yu、Matsumoto Masaki、Takami Tomoyo、Kobayashi Daiki、Yamanouchi Yoshinori、Araki Norie、Yoshizawa Akiyasu C、Tabata Tsuyoshi、Iwasaki Mio、Sugiyama Naoyuki、Tanaka Satoshi、Goto Susumu、Ishihama Yasushi
  • Journal Title: Nucl Acids Res Volume: 47 Pages: 1218-1224
  • DOI: 10.1093/nar/gky899
  • Peer Reviewed / Open Access
• [Journal Article] Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16 (2018)
  • Author(s): Hosokawa Hiroyuki、Romero-Wolf Maile、Yui Mary A.、Ungerb?ck Jonas、Quiloan Maria L. G.、Matsumoto Masaki、Nakayama Keiichi I.、Tanaka Tomoaki、Rothenberg Ellen V.
  • Journal Title: Nature Immunology Volume: 19 Pages: 1427-1440
  • DOI: 10.1038/s41590-018-0238-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of the physiological substrates of PDIp, a pancreas-specific protein-disulfide isomerase family member (2018)
  • Author(s): Fujimoto Takushi、Nakamura Orie、Saito Michiko、Tsuru Akio、Matsumoto Masaki、Kohno Kenji、Inaba Kenji、Kadokura Hiroshi
  • Journal Title: J Biol Chem Volume: 293 Pages: 18421-18433
  • DOI: 10.1074/jbc.ra118.003694
  • Peer Reviewed / Open Access
• [Journal Article] Trans-omic Analysis Reveals Selective Responses to Induced and Basal Insulin across Signaling, Transcriptional, and Metabolic Networks (2018)
  • Author(s): Kawata Kentaro、Hatano Atsushi、Yugi Katsuyuki、Kubota Hiroyuki、Sano Takanori、Fujii Masashi、Tomizawa Yoko、Kokaji Toshiya、Tanaka Kaori Y.、Uda Shinsuke、Suzuki Yutaka、Matsumoto Masaki、Nakayama Keiichi I.、Saitoh Kaori、Kato Keiko、Ueno Ayano、Ohishi Maki、Hirayama Akiyoshi、Soga Tomoyoshi、Kuroda Shinya
  • Journal Title: iScience Volume: 7 Pages: 212-229
  • DOI: 10.1016/j.isci.2018.07.022
  • Peer Reviewed / Open Access
• [Journal Article] Transcription Factor PU.1 Represses and Activates Gene Expression in Early T Cells by Redirecting Partner Transcription Factor Binding (2018)
  • Author(s): Hosokawa Hiroyuki、Ungerb?ck Jonas、Wang Xun、Matsumoto Masaki、Nakayama Keiichi I.、Cohen Sarah M.、Tanaka Tomoaki、Rothenberg Ellen V.
  • Journal Title: Immunity Volume: 48
  • DOI: 10.1016/j.immuni.2018.04.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth. (2018)
  • Author(s): M Morita, T Sato, M Nomura, Y Sakamoto, Y Inoue, R Tanaka, S Ito, K Kurosawa, K Yamaguchi, Y Sugiura, H Takizaki, Y Yamashita, R Katakura, I Sato, Y Okada, H Watanabe, G Kondoh, et al.
  • Journal Title: Cancer Cell Volume: 12 Pages: 355-367
  • DOI: 10.1016/j.ccell.2018.02.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The promise of targeted proteomics for quantitative network biology (2018)
  • Author(s): Matsumoto Masaki、Nakayama Keiichi I
  • Journal Title: Curr Opin Biotechnol. Volume: 54 Pages: 88-97
  • DOI: 10.1016/j.copbio.2018.02.014
  • Peer Reviewed
• [Journal Article] Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages (2017)
  • Author(s): Nakatsumi Hirokazu、Matsumoto Masaki、Nakayama Keiichi I.
  • Journal Title: Cell Rep. Volume: 21 Pages: 2471-2486
  • DOI: 10.1016/j.celrep.2017.11.014
  • Peer Reviewed / Open Access
• [Presentation] iMPAQT: a scalable and flexible platform for the quantification of proteins of interest (2018)
  • Author(s): 松本 雅記、中山 敬一
  • Organizer: 第91回日本生化学会
• [Presentation] iMPAQT ver.2.0: 拡張性と柔軟性を備えたタンパク質絶対定量プラットフォーム (2018)
  • Author(s): 松本 雅記、中山 敬一
  • Organizer: MSP2018
• [Presentation] Robotics promotes accurate and reproducible data acquisition in proteomics (2018)
  • Author(s): Masaki Matsumoto
  • Organizer: Robotics and Semantic Systems for Biology Symposium 2
  • Int'l Joint Research / Invited
• [Presentation] iMPAQT: A Platform for Large-Scale Targeted Proteomics Based on an in Vitro Human Proteome (2017)
  • Author(s): 松本雅記、中山敬一
  • Organizer: JPrOS2017年大会
• [Presentation] iMPAQT: A platform for large-scale targeted proteomics based on an in vitro human proteome (2017)
  • Author(s): 松本雅記
  • Organizer: 第65質量分析総合討論会
  • Invited