Elucidation of mechanisms of xCT-mediated cancer therapy resistance accompanied with metabolic reprograming and cancer stem cell property

• Project/Area Number: 21H02766
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Fujita Health University (2023); Keio University (2021-2022)
• Principal Investigator: Nagano Osamu 藤田医科大学, 腫瘍医学研究センター, 教授 (30404346)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2023: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2022: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: p62/SQSTM1 / xCT / 抗がん剤耐性 / オートファジー / フェロトーシス / がん幹細胞 / 治療抵抗性 / 肺がん / p62 / 小細胞肺がん / 小細胞肺癌 / 癌幹細胞

Outline of Research at the Start

当該研究では小細胞肺癌（SCLC）の悪性化に関わるp62/SQSTM1およびxCTの機能的役割を明らかにするため、① xCT発現が癌幹細胞性に与える影響の解析 ② p62/SQSTM1を介したxCTの発現制御機構 ③ 新規SCLCマウスモデルとxCT標的治療の開発に関する研究を行う。さらに、我々が最近開発した新規xCT阻害剤と併用剤による合成致死誘導療法の抗腫瘍効果についてマウスモデルを用いて解析することで臨床応用に向けた非臨床POCの取得を目指す。

Outline of Final Research Achievements

The initial standard treatment for small cell lung cancer (SCLC) is systemic chemotherapy with platinum drugs, but many patients experience relapse or disease progression. However, the mechanisms promoting resistance in relapsed/aggravated SCLC cells remain largely unknown. In this study, we demonstrated that the regulation of xCT expression via p62/SQSTM1 is involved in the progression of SCLC cells. Furthermore, we found that autophagy deficiency contributes to the cisplatin resistance of SCLC cells. Therefore, we searched for inhibitors to develop therapies targeting p62/SQSTM1 and identified promising candidates that can reduce the protein stability of p62/SQSTM1.

Academic Significance and Societal Importance of the Research Achievements

小細胞肺癌（SCLC）の初回標準治療はプラチナ製剤併用全身化学療法であるが、その多くが再発・増悪をきたす。しかしながら、再発・増悪したSCLC細胞の治療抵抗性を促進するメカニズムについてはほとんど分かっていない。このようにアンメットメディカルニーズが高いがん腫におけてp62/SQSTM1を介した治療抵抗性メカニズムを明らかにし、新たな候補薬を同定した。この薬剤が臨床応用されれば、SCLCやp62/SQSTM1を高発現する高悪性度のがんに対して新たな治療法の開発に繋がることが期待でき、広く社会に貢献することが可能になる。

Research Products

• [Journal Article] Mesothelial cells with mesenchymal features enhance peritoneal dissemination by forming a protumorigenic microenvironment (2024)
  • Author(s): Yonemura A、Semba T、Zhang J、Fan Y、Yasuda-Yoshihara N、Wang H、Uchihara T、Yasuda T、Nishimura A、Fu L、Hu X、Wei F、Kitamura F、Akiyama T、Yamashita K、Eto K、Iwagami S、Iwatsuki M、Miyamoto Y、Matsusaki K、Yamasaki J、Nagano O、Saya H、Song S、Tan P、Baba H、Ajani Jaffer A.、Ishimoto T
  • Journal Title: Cell Reports Volume: 43 Issue: 1 Pages: 113613-113613
  • DOI: 10.1016/j.celrep.2023.113613
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer (2023)
  • Author(s): Kitamura F、Semba T、Yasuda-Yoshihara N、Yamada K、Nishimura A、Yamasaki J、Nagano O、Yasuda T、Yonemura A、Tong Y、Wang H、Akiyama T、Matsumura K、Uemura N、Itoyama R、Bu L、Fu L、Hu X、Wei F、Mima K、Imai K、Hayashi H、Yamashita Y、Miyamoto Y、Baba H、Ishimoto T
  • Journal Title: JCI Insight Volume: 8 Issue: 20
  • DOI: 10.1172/jci.insight.163022
  • Peer Reviewed / Open Access
• [Journal Article] Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment (2023)
  • Author(s): Fan Y, Li Y, Yao X, Jin J, Scott A, Liu B, Wang S, Huo L, Wang Y, Wang R, Pool Pizzi M, Ma L, Shao S, Sewastjanow-Silva M, Waters R, Chatterjee D, Liu B, Shanbhag N, Peng G, Calin GA, Mazur PK, Hanash SM, Ishizawa J, Hirata Y, Nagano O, Wang Z, Wang L, Xian W, McKeon F, Ajani JA, Song S.
  • Journal Title: Gut Volume: 72 Issue: 4 Pages: 624-637
  • DOI: 10.1136/gutjnl-2021-326581
  • Peer Reviewed
• [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] Presence of spontaneous epithelial-mesenchymal plasticity in esophageal cancer (2022)
  • Author(s): Tsuchihashi Kenji、Hirata Yuki、Yamasaki Juntaro、Suina Kentaro、Tanoue Kenro、Yae Toshifumi、Masuda Kenta、Baba Eishi、Akashi Koichi、Kitagawa Yuko、Saya Hideyuki、Nagano Osamu
  • Journal Title: Biochemistry and Biophysics Reports Volume: 30 Pages: 101246-101246
  • DOI: 10.1016/j.bbrep.2022.101246
  • 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
• [Presentation] がんのフェロトーシス回避機構と新規治療法の開発 (2024)
  • Author(s): 永野修
  • Organizer: 第38回 Wakoワークショップ 「シン・がん医療：新技術に裏打ちされたがんの基礎と臨床」
  • Invited
• [Presentation] がんの進展におけるxCTを介したアミノ酸輸送の役割 (2023)
  • Author(s): 永野修
  • Organizer: 第96回日本生化学会大会
  • Invited
• [Presentation] がん転移におけるフェロトーシス抵抗性 (2022)
  • Author(s): 永野修
  • Organizer: 第31回日本がん転移学会学術集会・総会
  • Invited
• [Presentation] シスチントランスポーターxCTとALDHを標的とした新しいがん治療 (2022)
  • Author(s): 永野修
  • Organizer: 日本薬物動態学会第37回年会
  • Invited
• [Presentation] Development of cancer therapy by simultaneous targeting of cystine-glutamate antiporter xCT and aldehyde dehydrogenase (2022)
  • Author(s): Osamu Nagano
  • Organizer: The Cold Spring Harbor Asia conference on Iron, Reactive Oxygen Species & Ferroptosis in Life, Death & Disease, AWAJI, JAPAN
  • Int'l Joint Research / Invited
• [Presentation] Novel approach for cancer therapy by simultaneous targeting of xCT-dependent cystine transport and aldehyde dehydrogenase activity (2022)
  • Author(s): Osamu Nagano
  • Organizer: Redox Week in Sendai 2022
  • Int'l Joint Research / Invited
• [Presentation] Therapeutic targeting of redox system in cancer stem cells (2021)
  • Author(s): 永野修
  • Organizer: 第80回日本癌学会学術総会
  • Invited