Development of a novel mouse model of gastric cancer and elucidation of the molecular mechanisms that induce the intestinal-type to diffuse-type transition.

• Project/Area Number: 22K20836
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Fujita Health University (2023); Keio University (2022)
• Principal Investigator: Yamasaki Juntaro 藤田医科大学, がん医療研究センター, 研究員 (10963580)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 胃がん / 転移 / 浸潤 / 胃癌 / マウスモデル

Outline of Research at the Start

胃がんの組織型は大きく分けて腸型、びまん型、両者が混在する混合型が存在する。また以前から、胃がん細胞が性質変化を起こすことで腸型からびまん型/混合型へと組織型が移行する可能性が示唆されているが、その機序については明らかになっていない。本研究ではこれまで樹立したマウス胃腫瘍由来オルガノイド(腸型)に対してびまん型胃がんに特異的な遺伝子変異を導入し、浸潤や腹膜播種を伴うびまん型胃がんの組織型を示す新規モデルを樹立することで腸型からびまん型/混合型が発生する分子メカニズムや浸潤・転移に重要な分子を明らかにする。

Outline of Final Research Achievements

This study established a novel diffuse-type gastric cancer mouse cell line by knocking out Cdh1, which frequently mutates in diffuse-type gastric cancer, in the mouse gastric cancer cell line GAN-KP that forms intestinal-type gastric cancer. A mouse model using the Cdh1-knockout gastric cancer cells (GAN-KPC) was created, and comparisons with the original intestinal-type gastric cancer cells (GAN-KP) suggested that the knockout of Cdh1 promotes invasion and metastasis. Additionally, the study evaluated the differences in sensitivity to major anticancer drugs and metabolic characteristics, indicating that the knockout of Cdh1 contributes to an increased dependence on glycolysis and a decrease in ferroptosis sensitivity.

Academic Significance and Societal Importance of the Research Achievements

胃がんの組織型は大きく分けてIntestinal-type (腸型)、Diffuse-type (びまん型)、両者が混在するMixed-type (混合型)が存在し、中でも細胞の未分化性が高く頻繁に腹膜播種を引き起こすDiffuse-typeは、とくに予後不良になることが知られている。本研究で新たに樹立されたびまん型胃がんマウスモデルは免疫が正常な同系マウスに同所移植されたもので、免疫細胞や腫瘍微小環境との相互作用を明らかにするための有用なモデルであり、びまん型胃がんの好転移性メカニズムの解明や治療標的の探索に用いることで、予後不良なびまん型胃がんに対する新たな治療薬の開発に貢献しうる。

Research Products

• [Journal Article] RAC1-mediated integrin alpha-6 expression in E-cadherin-deficient gastric cancer cells promotes interactions with the stroma and peritoneal dissemination (2024)
  • Author(s): Zhang Jun、Fu Lingfeng、Wang Huaitao、Yonemura Atsuko、Semba Takashi、Yasuda-Yoshihara Noriko、Nishimura Akiho、Tajiri Takuya、Tong Yilin、Yasuda Tadahito、Uchihara Tomoyuki、Yamazaki Masaya、Okamoto Yuya、Yamasaki Juntaro、Nagano Osamu、Baba Hideo、Ishimoto Takatsugu
  • Journal Title: Cancer Letters Volume: 591 Pages: 216901-216901
  • DOI: 10.1016/j.canlet.2024.216901
  • Peer Reviewed
• [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] A novel tdTomato transgenic mouse model to visualize FAP‐positive cancer‐associated fibroblasts (2023)
  • Author(s): Wei F , Uchihara T , Yonemura A , Yasuda-Yoshihara N , Yasuda T , Semba T , Fukuda M , Akiyama T , Kitamura F , Kariya R , Yamasaki J , Aihara K , Yamashita K , Nagano O , Okada S , Baba H , Ishimoto T
  • Journal Title: The FEBS Journal Volume: - Issue: 10 Pages: 2604-2615
  • DOI: 10.1111/febs.16712
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Angiopoietin-like 4 promotes glucose metabolism by regulating glucose transporter expression in colorectal cancer (2022)
  • Author(s): Mizuno Shodai、Seishima Ryo、Yamasaki Juntaro、Hattori Kaoru、Ogiri Masayo、Matsui Shimpei、Shigeta Kohei、Okabayashi Koji、Nagano Osamu、Li Liang、Kitagawa Yuko
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: 148 Issue: 6 Pages: 1351-1361
  • DOI: 10.1007/s00432-022-03960-z
• [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] 膵癌腫瘍関連線維芽細胞における乳酸代謝の役割についての検討 (2023)
  • Author(s): 山田 晃亮、北村 文優、千場 隆、魏 峰、永野 修、 西村 朗甫、トン 依霖、安田 忠仁、安田 法子、山崎 淳太郎、米村 敦子、馬場 秀夫、石本 崇胤
  • Organizer: 日本癌学会総会
• [Presentation] 新規マウスモデルを用いた高異型度漿液性癌の予後不良に関連するバイオマーカーの同定 (2023)
  • Author(s): 今枝 慶蓉、増田 健太、永井 晋平、田村 友宏、杉原 英志、山崎 淳太郎、大槻 雄士、信末 博行、千代田 達幸、小林 佑介、 阪埜 浩司、青木 大輔、山上 亘、佐谷 秀行、永野 修
  • Organizer: 日本癌学会総会
• [Presentation] MEKの阻害がKRAS遺伝子変異胃癌の転移性進行を抑制する (2022)
  • Author(s): 山崎淳太郎
  • Organizer: 第81回日本癌学会学術総会