Elucidation of the interaction between tumor epithelial cells and stromal cells in acquiring resistance to molecular-targeted drugs

• Project/Area Number: 16K07139
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: FUJISHITA Teruaki 愛知県がんセンター(研究所), がん病態生理学分野, 主任研究員 (50511870)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 大腸がん / がん微小環境 / 治療抵抗性 / 癌 / 遺伝子 / 薬理学

Outline of Final Research Achievements

Although molecular-targeted therapy has become a standard therapy for many cancer types, solid tumors acquire resistance against the targeted therapy in most cases. In this study, I investigated the possibility that the tumor microenvironment could be a therapeutic target for colorectal cancer that acquired resistance against targeted therapy. Colorectal cancer tissues that acquired mTOR-inhibitor resistance showed elevated levels of cytokines via MAP kinase pathway activation in the stromal cells building the tumor microenvironment. Because the mTOR-inhibitor resistance of colorectal cancer was abolished by suppression of the activated tumor microenvironment using a MEK inhibitor, the tumor microenvironment is considered a clue for overcoming resistance against targeted therapies.

Academic Significance and Societal Importance of the Research Achievements

標的分子の変異やフィードバック経路の活性化などがん細胞が分子標的薬に対して抵抗性を獲得する方法は様々であり、これまでがん細胞そのものにおける抵抗性獲得機序が研究の対象とされて来た。がん微小環境もまた抵抗性獲得に密接に関与していることが本研究により明らかにされたことで、がん細胞だけでなくがん微小環境を標的とした分子標的薬抵抗性がんの新たな治療戦略の開発に貢献するものと期待される。

Research Products

• [Journal Article] TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation. (2019)
  • Author(s): Matsushita A, Sato T, Mukai S, Fujishita T, Mishiro-Sato E, Okuda M, Aoki M, Hasegawa Y, Sekido Y
  • Journal Title: Oncogene Volume: 38 Issue: 11 Pages: 1966-1978
  • DOI: 10.1038/s41388-018-0417-7
  • Peer Reviewed / Open Access
• [Journal Article] Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC (2017)
  • Author(s): Satoh K, Yachida S, Sugimoto M, Oshima M, Nakagawa T, Akamoto S, Tabata S, Saitoh K, Kato K, Sato S, Igarashi K, Aizawa Y, Kajino-Sakamoto R, Kojima Y, Fujishita T, Enomoto A, Hirayama A, Ishikawa T, Taketo MM, Kushida Y, Haba R, Okano K, Tomita M, Suzuki Y, Fukuda S, Aoki M, Soga T.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 114 Issue: 37
  • DOI: 10.1073/pnas.1710366114
  • Peer Reviewed
• [Journal Article] Tumor microenvironment confers mTOR inhibitor resistance in invasive intestinal adenocarcinoma (2017)
  • Author(s): Fujishita T, Kojima Y, Kajino-Sakamoto R, Taketo MM, Aoki M.
  • Journal Title: Oncogene Volume: 36 Issue: 46 Pages: 6480-6489
  • DOI: 10.1038/onc.2017.242
  • Peer Reviewed
• [Presentation] 大腸がんのmTOR阻害薬抵抗性獲得にヒスタミンが関与している (2018)
  • Author(s): 藤下 晃章、小島 康 、三城 恵美、曽我 朋義、武藤 誠、青木 正博
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 大腸がん形成におけるDio2の役割 (2018)
  • Author(s): 小島 康 、藤下 晃章、三城 恵美、梶野 リエ、武藤 誠、青木 正博
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Apc変異マウスの腸管腫瘍形成において腸上皮細胞のMyD88が果たす役割の解明 (2018)
  • Author(s): 梶野 リエ、藤下 晃章、武藤 誠、青木 正博
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Roles of EGFR activation in drug resistance of intestinal tumors (2017)
  • Author(s): 藤下 晃章、津田 都子、小島 康、武藤 誠、青木 正博
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Combination treatment with erlotinib and trametinib suppresses intestinal adenocarcinoma formation in cis- Apc/Smad4 mice (2017)
  • Author(s): 津田 都子、藤下 晃章、小島 康、武藤 誠、青木 正博
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Role of intestinal epithelial MyD88 in intestinal tumorigenesis in Apc mice (2017)
  • Author(s): 梶野 リエ、藤下 晃章、武藤 誠、青木 正博
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Tumor microenvironment confers mTOR inhibitor resistance to invasive intestinal adenocarcinoma (2016)
  • Author(s): 藤下 晃章、梶野 リエ、小島 康、武藤 誠、青木 正博
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Role of Deiodinase, lodothyronine, TypeIIin Colon Tumorigenesis (2016)
  • Author(s): 小島 康、今度 ゆり子、藤下 晃章、梶野 リエ、武藤 誠、青木 正博
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Elucidation of the relevance of JNK-mTORC1 pathway activation to neuropeptides during intestinal tumorigenesis (2016)
  • Author(s): 梶野 リエ、藤下 晃章、武藤 誠、青木 正博
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-06
• [Remarks] 大腸がんが薬剤抵抗性を獲得する新しいメカニズムの発見
  • URL: https://www.pref.aichi.jp/cancer-center/ri/01bumon/07bunshi_byotai/index.html