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The elucidation of YAP/TAZ-mediated acquisition of diversity in pancreatic cancer cancer-associated fibroblasts and mechanisms of cancer progression

Research Project

Project/Area Number 21K15534
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionKumamoto University

Principal Investigator

Yamao Takanobu  熊本大学, 大学院生命科学研究部(医), 特定研究員 (70836337)

Project Period (FY) 2021-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords高血糖 / 膵がん / がん関連線維芽細胞(CAFs) / YAP/TAZ / がん微小環境 / 抗がん剤抵抗性 / Hyperglycemia / 膵癌 / CAFs / 腫瘍微小環境 / 癌関連線維芽細胞
Outline of Research at the Start

癌の微小環境を形成するメカニズムにおいて癌関連線維芽細胞(CAF)は癌細胞の癌悪性度ならびに細胞外マトリックスの蓄積や腫瘍免疫の抑制に関与し、様々な多様性(heterogeneity)を有することも注目されている。多くの固形癌において腫瘍抑制系シグナルHippopathwayの破綻による下流の転写因子(YAP/TAZ)の発現上昇が報告されているが、YAP/TAZを介したCAFのheterogeneityに関する研究は皆無であり本研究は極めて独創的である。得られる研究成果は腫瘍間質をターゲットとした分子標的の創出につながり臨床的意義は大きいと考えられる。

Outline of Final Research Achievements

We have elucidated the mechanism of tumor cell progression in pancreatic cancer based on hyperglycemia and YAP/TAZ signaling. First, in vitro experiments showed that hyperglycemia in tumor cell lines augments resistance to anticancer drugs via YAP/TAZ protein expression, and in vivo experiments showed that hyperglycemia induces an increase in tumor size by subcutaneous and orthotopic transplantation of human cell lines using mice. In addition, hyperglycemia was found to increase tumor size in mice. In addition, hyperglycemia activates not only tumor cells but also cancer-associated fibroblasts. At the same time, YAP/TAZ inhibitors suppress fibrosis and may contribute to the suppression of cancer progression in the pancreatic cancer microenvironment. These findings suggest that hyperglycemia regulates cancer progression via YAP/TAZ signaling in pancreatic cancer.

Academic Significance and Societal Importance of the Research Achievements

世界における死亡率第4位である膵がんは、根治切除後も再発率が高く予後不良であり、有効な化学療法や分子標的治療薬も限られている。近年、免疫チェックポイント阻害薬の開発は幅広い固形癌の治療成績向上に寄与してきたが膵がんにおいてはその適応は非常に限られている。YAP /TAZシグナルはがん細胞のみならずがん細胞周囲の微小環境においても浸潤・転移といった癌悪性度に寄与することが注目されており、今回我々が解明した高血糖状態におけるYAP /TAZシグナルを介したがん進展メカニズムは膵がんおよびがん微小環境をターゲットとした新規治療薬の開発に寄与することが期待される。

Report

(3 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (5 results)

All 2023 2022 2021

All Journal Article (2 results) (of which Peer Reviewed: 2 results) Presentation (3 results)

  • [Journal Article] Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer.2023

    • Author(s)
      Liu Z,
    • Journal Title

      Br J Cancer.

      Volume: 128(5) Issue: 5 Pages: 844-856

    • DOI

      10.1038/s41416-022-02106-9

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cancer-associated fibroblast senescence and its relation with tumour-infiltrating lymphocytes and PD-L1 expressions in intrahepatic cholangiocarcinoma2022

    • Author(s)
      2.Lan C, Kitano Y, Yamashita YI, Yamao T, Kajiyama K, Yoshizumi T, Fukuzawa K, Sugimachi K, Ikeda Y, Takamori H, Miyanari N, Hirota M, Baba H
    • Journal Title

      British Journal of Cancer

      Volume: 126 Issue: 2 Pages: 219-227

    • DOI

      10.1038/s41416-021-01569-6

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed
  • [Presentation] Hyperglycemia induces metabolic reprogramming and promotes epithelial-mesenchymal transitions in pancreatic cancer: An in vitro and in vivo experiment2023

    • Author(s)
      Zhao Liu, Hiromitsu Hayashi, Kazuki Matsumura, Yoko Ogata, Hiroki Sato, Yuta Shiraishi, Norio Uemura, Tatsunori Miyata, Takaaki Higashi, Shigeki Nakagawa, Kosuke Mima, Katsunori Imai, and Hideo Baba
    • Organizer
      AACR Annual Meeting 2023
    • Related Report
      2022 Annual Research Report
  • [Presentation] Hyperglycemia promotes epithelial mesenchymal transition in pancreatic cancer via YAP1/TAZ mediated metabolic changes2022

    • Author(s)
      柳昭、林洋光、佐藤寛紀、白石裕太、松村和季、上村紀雄、馬場秀夫
    • Organizer
      第 33 回日本消化器癌発生学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Hyperglycemia promotes epithelial mesenchymal transition in pancreatic cancer via YAP1/TAZ mediated metabolic changes2021

    • Author(s)
      林 洋光、松村 和季、北村 文優、甲斐田剛佳、中川茂樹、美馬浩介、今井 克憲、山下 洋市、馬場 秀夫
    • Organizer
      第80回日本癌学会学学術総会
    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2024-01-30  

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