Elucidation of cancer treatment resistance mechanism based on methionine metabolism and identification of novel therapeutic targets

• Project/Area Number: 21K19416
• 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: Fujita Health University (2022); Keio University (2021)
• Principal Investigator: Saya Hideyuki 藤田医科大学, がん医療研究センター, センター長 (80264282)
• Co-Investigator(Kenkyū-buntansha): 大槻 雄士 藤田医科大学, 医科学研究センター, 研究員 (10875412)
• 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: 難治がん / シスチントランスポーター / メチオニン代謝 / レドックス制御 / xCT / ALDH / フェロトーシス / 治療抵抗性 / 治療抵抗性がん / 活性酸素 / メチオニン

Outline of Research at the Start

がん細胞は外的・内的なストレスに対応して細胞の代謝系を変更することで増殖や生存に適切な環境を取得する能力を持つ。申請者らは長年にわたり、難治性がんにおけるアミノ酸代謝変化と抗酸化機構を標的としたがん治療の開発を行い、多くのがんを抑制できる阻害剤の組み合わせ（xCT阻害剤とALDH阻害剤）を明らかにした。しかし、細胞によってはこれらの組み合わせでもメチオニン代謝を利用することで細胞死を回避する能力があることを見出している。メチオニン代謝を詳細に解析することで難治性がんを特異的に駆逐できる強力かつ安全な治療を考案することを本研究の目的とする。

Outline of Final Research Achievements

A cystine transporter inhibitor sulfasalazine can specifically eliminate treatment-resistant cancer stem cells, but it is known that resistance eventually develops. Therefore, we generated cancer cells resistant to sulfasalazine and comprehensively investigated their methionine metabolism and gene methylation. We found that methionine metabolism was enhanced in the resistant cells, and that specific genes were highly methylated. In addition, the genes related to ALDH metabolism were highly methylated. It became clear that there is a possibility that increased methionine metabolism strengthens redox regulation as well as enhances detoxification by ALDH, avoiding cell death.

Academic Significance and Societal Importance of the Research Achievements

申請者らの研究チームは、シスチントランスポーターとALDHを同時に阻害することで腫瘍細胞に特異的かつ強力にフェロトーシスが誘導できることを見出し、その発見に基づいた医師主導治験の準備を進めている。大多数のがん細胞に対してこの薬剤併用は有効であることが確認できているが、投与を継続することによって耐性が生じる可能性は否めない。本研究ではシスチントランスポーターを抑制した際にメチオニン代謝によって細胞死を回避する機構が発動することが明確となり、耐性機構に対する対抗策を講じることが可能となった。

Research Products

• [Journal Article] Stromal reprogramming through dual PDGFRα/β blockade boosts the efficacy of anti-PD-1 immunotherapy in fibrotic tumors. (2022)
  • Author(s): T. Akiyama, T. Yasuda, T. Uchihara, N. Yasuda-Yoshihara, BJY. Tan, A. Yonemura, T. Semba, J. Yamasaki, Y. Komohara, K. Ohnishi, F. Wei, L. Fu, J. Zhang, F. Kitamura, K. Yamashita, K. Eto, S. Iwagami, H. Tsukamoto, T. Umemoto, M. Masuda, O. Nagano, Y. Satou, H. Saya, P. Tan, H. Baba, T. Ishimoto
  • Journal Title: Cancer Res. Volume: 83 Issue: 5 Pages: 753-770
  • DOI: 10.1158/0008-5472.can-22-1890
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pigment epithelium-derived factor promotes peritoneal dissemination of ovarian cancer through induction of immunosuppressive macrophages (2022)
  • Author(s): Ueno Sayaka、Sudo Tamotsu、Saya Hideyuki、Sugihara Eiji
  • Journal Title: Communications Biology Volume: 5 Issue: 1 Pages: 904-919
  • DOI: 10.1038/s42003-022-03837-4
  • Peer Reviewed / Open Access
• [Journal Article] MEK inhibition suppresses metastatic progression of <i>KRAS</i> ‐mutated gastric cancer (2022)
  • Author(s): Yamasaki Juntaro、Hirata Yuki、Otsuki Yuji、Suina Kentaro、Saito Yoshiyuki、Masuda Kenta、Okazaki Shogo、Ishimoto Takatsugu、Saya Hideyuki、Nagano Osamu
  • Journal Title: Cancer Science Volume: 113 Issue: 3 Pages: 916-925
  • DOI: 10.1111/cas.15244
  • Peer Reviewed / Open Access
• [Journal Article] TGFβ Signaling Activated by Cancer-Associated Fibroblasts Determines the Histological Signature of Lung Adenocarcinoma (2021)
  • Author(s): Sato Ryo、Imamura Kosuke、Semba Takashi、Tomita Yusuke、Saeki Sho、Ikeda Koei、Komohara Yoshihiro、Suzuki Makoto、Sakagami Takuro、Saya Hideyuki、Arima Yoshimi
  • Journal Title: Cancer Research Volume: 81 Issue: 18 Pages: 4751-4765
  • DOI: 10.1158/0008-5472.can-20-3941
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer (2021)
  • Author(s): Kenichi Miyata, Yoshinori Imai, Satoshi Hori, Mika Nishio, Tze Mun Loo, Ryo Okada, Liying Yang, Tomoyoshi Nakadai, et. al.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 118 Issue: 35
  • DOI: 10.1073/pnas.2025647118
  • Peer Reviewed / Open Access
• [Journal Article] Lactate Reprograms Energy and Lipid Metabolism in Glucose-Deprived Oxidative Glioma Stem Cells (2021)
  • Author(s): Minami Noriaki、Tanaka Kazuhiro、Sasayama Takashi、Kohmura Eiji、Saya Hideyuki、Sampetrean Oltea
  • Journal Title: Metabolites Volume: 11 Issue: 5 Pages: 325-325
  • DOI: 10.3390/metabo11050325
  • Peer Reviewed / Open Access / Int'l Joint Research