Elucidation of metabolointeractome in tumor microenvironments

• Project/Area Number: 21K19399
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Osawa Tsuyoshi 東京大学, 先端科学技術研究センター, 准教授 (50567592)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: がん / 代謝 / 細胞間相互作用 / アミノ酸 / オミクス統合解析

Outline of Research at the Start

がんの転移・浸潤・薬剤耐性などの悪性化には腫瘍微小環境が重要な役割を果たす。申請者は、腫瘍微小環境において、分岐鎖アミノ酸のがん細胞への供給が、線維芽細胞や間質細胞からなされる新たなメカニズムが存在する可能性を見出している。本研究では、アミノ酸を軸とした腫瘍組織における細胞間相互作用で鍵となる代謝物（メタボロインタラクト―ム）の探索的な研究から新規がんの治療法の開発につながる研究を目的とする。本研究は、がん研究のみならず、アミノ酸代謝疾患研究、栄養学研究、mTOR研究などの学術体系の変革や転換にも繋がる可能性を有し、がんを克服する画期的な代謝疾患の制御法を開発など、挑戦的な研究である。

Outline of Final Research Achievements

The tumor microenvironment plays an important role in malignant tumor such as metastasis, invasion, and drug resistance. In this research we found a novel mechanism by which branched-chain amino acids are supplied to cancer cells from fibroblasts and stromal cells in the tumor microenvironment. In addition, we found amino acids as key metabolic interaction between cancer and fibroblast (metabolo-interactome) in tumor tissues evaluated by following two research topics: (1) exploration of key cell-cell interactions in the tumor microenvironment and (2) elucidation of the metabolic interactions within tumor microenvironment. We have identified potential nutrient sensing/regulation factors that may lead to the development of novel cancer therapies, and have also elucidated a novel nutrient supply mechanism in tumor.

Academic Significance and Societal Importance of the Research Achievements

本研究は、アミノ酸を軸とした腫瘍組織における細胞間相互作用で鍵となる代謝物（メタボロインタラクト―ム）の探索的な研究から新規がんの治療法の開発につながる研究を目的とした。本研究は、がん研究のみならず、アミノ酸代謝疾患研究、栄養学研究、mTOR研究などの学術体系の変革や転換にも繋がる可能性を有し、がんを克服する画期的な代謝疾患の制御法を開発に繋がる研究である。また、本研究は、申請者が持つ独自のアミノ酸培養系で、これまで他の栄養素の作用が混在し解析が困難であった１代謝物に起因する系統的な多階層オミクス解析で実現し、がん細胞の生存や幹細胞性維持や腫瘍組織の細胞間相互作用の鍵代謝物の同定に繋がった

Research Products

• [Journal Article] Convergent Genomic Diversity and Novel BCAA Metabolism in Intrahepatic Cholangiocarcinoma (2023)
  • Author(s): Kitagawa A, Osawa T, Noda M, Kobayashi Y, et al. and Mimori K.
  • Journal Title: Br. J. Cancer Volume: -
  • Peer Reviewed
• [Journal Article] Cancer Metabolism within the Tumor Microenvironments (2023)
  • Author(s): Aki S, Nakahara R, Maeda K, Osawa T
  • Journal Title: BBA Volume: -
  • Peer Reviewed
• [Journal Article] Metabolic adaptations of cancer in extreme tumor microenvironments (2023)
  • Author(s): Ryuichi Nakahara、Keisuke Maeda、Sho Aki、Tsuyoshi Osawa
  • Journal Title: Cancer Science Volume: 114 Issue: 4 Pages: 1200-1207
  • DOI: 10.1111/cas.15722
  • Peer Reviewed / Open Access
• [Journal Article] NRF3 activates mTORC1 arginine-dependently for cancer cell viability (2023)
  • Author(s): Hirose Shuuhei、Waku Tsuyoshi、Tani Misato、Masuda Haruka、Endo Keiko、Ashitani Sanae、Aketa Iori、Kitano Hina、Nakada Sota、Wada Ayaka、Hatanaka Atsushi、Osawa Tsuyoshi、Soga Tomoyoshi、Kobayashi Akira
  • Journal Title: iScience Volume: 26 Issue: 2 Pages: 106045-106045
  • DOI: 10.1016/j.isci.2023.106045
  • Peer Reviewed / Open Access
• [Journal Article] Pathological complete remission of relapsed tumor by photo‐activating antibody-mimetic drug conjugate treatment (2022)
  • Author(s): Kaneko Yudai、Yamatsugu Kenzo、Yamashita Takefumi、Takahashi Kazuki、Tanaka Toshiya、Aki Sho、Tatsumi Toshifumi、Kawamura Takeshi、Miura Mai、Ishii Masazumi、Ohkubo Kei、Osawa Tsuyoshi、Kodama Tatsuhiko、Ishikawa Shumpei、Tsukagoshi Masanobu、Chansler Michael、Sugiyama Akira、Kanai Motomu、Katoh Hiroto
  • Journal Title: Cancer Science Volume: 113 Issue: 12 Pages: 4350-4362
  • DOI: 10.1111/cas.15565
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors (2022)
  • Author(s): Melvin Pan、Christiane Zorbas、Maki Sugaya、Kensuke Ishiguro、Miki Kato、Miyuki Nishida、Hai-Feng Zhang、Marco M. Candeias、Akimitsu Okamoto、Takamasa Ishikawa、Tomoyoshi Soga、Hiroyuki Aburatani、Juro Sakai、Yoshihiro Matsumura、Tsutomu Suzuki、Christopher G. Proud、Denis L. J. Lafontaine、Tsuyoshi Osawa
  • Journal Title: Nature Communications Volume: 13(1) Issue: 1 Pages: 3706-3706
  • DOI: 10.1038/s41467-022-31418-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metagenomic identification of microbial signatures predicting pancreatic cancer from a multinational study (2022)
  • Author(s): Nagata N, Nishijima S, Kojima Y, Hisada Y, Imbe K, Miyoshi-Akiyama T, Suda W, Kimura M, Aoki R, Sekine K, Ohsugi M, Miki K, Osawa T, Ueki T, Oka S, Mizokami M, Kartal E, Schmidt TSB, Molina-Montes E, Estudillo L, Malats N, Trebicka J, Kersting S, Langheinrich M, Bork P, Uemura N, Itoi T, and Kawai T
  • Journal Title: Gastroenterology Volume: 163 Issue: 1 Pages: 222-238
  • DOI: 10.1053/j.gastro.2022.03.054
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis (2022)
  • Author(s): Murakami K, Sasaki Y, Asahiyama M, Yano W, Takizawa T, Kamiya W, Matsumura Y, Anai M, Osawa T, Fruchart JC, Fruchart-Najib J, Aburatani H, Sakai J, Kodama T, Tanaka T.
  • Journal Title: Cells Volume: 11 Issue: 4 Pages: 720-720
  • DOI: 10.3390/cells11040720
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Antibody mimetic drug conjugate manufactured by high-yield Escherichia coli expression and non-covalent binding system (2022)
  • Author(s): Yamatsugu Kenzo、Katoh Hiroto、Yamashita Takefumi、Takahashi Kazuki、Aki Sho、Tatsumi Toshifumi、Kaneko Yudai、Kawamura Takeshi、Miura Mai、Ishii Masazumi、Ohkubo Kei、Osawa Tsuyoshi、Kodama Tatsuhiko、Ishikawa Shumpei、Kanai Motomu、Sugiyama Akira
  • Journal Title: Protein Expression and Purification Volume: 192 Pages: 106043-106043
  • DOI: 10.1016/j.pep.2021.106043
  • Peer Reviewed / Open Access
• [Journal Article] Metagenomic identification of microbial signatures predicting pancreatic cancer from a multinational study (2022)
  • Author(s): Nagata N et al.
  • Journal Title: Gastroenterology Volume: -
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis (2022)
  • Author(s): Murakami K et al.
  • Journal Title: Cells Volume: -
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Antibody mimetic drug conjugate manufactured by high-yield Escherichia coli expression and non-covalent binding system (2022)
  • Author(s): Yamatsugu K et al.
  • Journal Title: Protein Expr Purif. Volume: - Pages: 106043-106043
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever (2021)
  • Author(s): Yoneshiro T, Kataoka N, Walejko JM, Ikeda K, Brown Z, Yoneshiro M, Crown SB, Osawa T, Sakai J, McGarrah RW, White PJ, Nakamura K, Kajimura S.
  • Journal Title: Elife Volume: 10
  • DOI: 10.7554/elife.66865
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of Down syndrome critical region-1 leads to cholesterol metabolic dysfunction that exaggerates hypercholesterolemia in ApoE-null background (2021)
  • Author(s): Muramatsu Masashi、Osawa Tsuyoshi、Miyamura Yuri、Nakagawa Suguru、Tanaka Toshiya、Kodama Tatsuhiko、Aburatani Hiroyuki、Sakai Juro、Ryeom Sandra、Minami Takashi
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100697-100697
  • DOI: 10.1016/j.jbc.2021.100697
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma. (2021)
  • Author(s): Shirai K, Nagae G, Seki M, Kudo Y, Kamio A, Hayashi A, Okabe A, Ota S, Tsutsumi S, Fujita T, Yamamoto S, Nakaki R, Kanki Y, Osawa T, Midorikawa Y, Tateishi K, Ichinose M, Aburatani H.
  • Journal Title: Cancer Sci. Volume: 112 Issue: 7 Pages: 2855-2869
  • DOI: 10.1111/cas.14897
  • Peer Reviewed / Open Access
• [Journal Article] Floxuridine Oligomers Activated under Hypoxic Environment (2021)
  • Author(s): Morihiro, K.; Ishinabe, T.; Takatsu, M.; Osumi, H.; Osawa, T.; Okamoto, A.
  • Journal Title: J. Am. Chem. Soc. Volume: 143 Issue: 9 Pages: 3340-3347
  • DOI: 10.1021/jacs.0c10732
  • Peer Reviewed / Open Access
• [Presentation] 腫瘍微小環境における免疫細胞を介した代謝適応機構 (2023)
  • Author(s): 大澤毅
  • Organizer: 第7回理論生物学ワークショップ
  • Invited
• [Presentation] Cancer Metabolism within tumor microenvironments (2022)
  • Author(s): Tsuyoshi Osawa
  • Organizer: 12th AACR-JCA Joint Conference
  • Int'l Joint Research / Invited
• [Presentation] 腫瘍微小環境における代謝変化を抑制するオルガネラダイナミクス (2022)
  • Author(s): 大澤毅
  • Organizer: 第81回日本癌学会学術総会
  • Invited
• [Presentation] がんと代謝2022 (Years in Review) (2022)
  • Author(s): 大澤毅
  • Organizer: 第81回日本癌学会学術総会
  • Invited
• [Presentation] 肝内胆管がんのゲノム多様性を凌駕しておこるBCAA代謝機構 (2022)
  • Author(s): 大澤毅
  • Organizer: 第26回日本がん分子標的治療学会学術集会
  • Invited
• [Presentation] 腫瘍微小環境における特異的な代謝リプログラミング (2022)
  • Author(s): 大澤毅
  • Organizer: 第22回日本抗加齢医学会総会
  • Invited
• [Presentation] ニュートリオミクスから迫るオルガネラダイナミクス (2022)
  • Author(s): 大澤毅
  • Organizer: iSeminar (異分野融合セミナー)
  • Invited
• [Presentation] 造血細胞、エクソソーム、多階層オミクス解析からみる全身性疾患生物学 (2021)
  • Author(s): 大澤毅
  • Organizer: 94回日本生化学会
  • Invited
• [Presentation] がん微小環境におけるがん細胞と線維芽細胞の代謝相互作用 (2021)
  • Author(s): 大澤毅
  • Organizer: 第80回日本癌学会学術総会
  • Invited
• [Presentation] ニュートリオミクスから迫るがん悪性化機構の解明 (2021)
  • Author(s): 大澤毅
  • Organizer: 第121回北海道癌談話会春季シンポジウム
  • Invited
• [Presentation] ニュートリオミクス、がんと代謝 (2021)
  • Author(s): 大澤毅
  • Organizer: 第２５回日本がん分子標的治療学会学術集会
  • Invited
• [Presentation] がん微小環境におけるエピジェネティック制御 (2021)
  • Author(s): 大澤毅
  • Organizer: 第１４回日本エピジェネティクス研究会
  • Invited
• [Book] 疾患原因遺伝子・タンパク質の解析技術と創薬/診断技術への応用 (2022)
  • Author(s): 執筆者：81名、技術情報協会
  • Total Pages: 530
  • Publisher: 技術情報協会
  • ISBN: 9784861048777
• [Remarks] -
  • URL: https://www.onc.rcast.u-tokyo.ac.jp/ja/
• [Patent(Industrial Property Rights)] 含フッ素アミノ酸 (2022)
  • Inventor(s): 大澤毅ら
  • Industrial Property Rights Holder: 大澤毅ら
  • Industrial Property Rights Type: 特許
  • Filing Date: 2022
• [Patent(Industrial Property Rights)] 横紋筋肉腫の検出方法およびそのバイオマーカー (2022)
  • Inventor(s): 大澤毅ら
  • Industrial Property Rights Holder: 大澤毅ら
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2022-168633
  • Filing Date: 2022
• [Patent(Industrial Property Rights)] 神経芽腫の診断に用いる新たな尿中代謝物 (2022)
  • Inventor(s): 大澤毅ら
  • Industrial Property Rights Holder: 大澤毅ら
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2022-010494
  • Filing Date: 2022
• [Patent(Industrial Property Rights)] 検体チューブ及び分注デッキ (2021)
  • Inventor(s): 大澤毅ら
  • Industrial Property Rights Holder: 大澤毅ら
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-055060
  • Filing Date: 2021