Regulatory mechanisms of cell-cell interactions mediated by ANGPTL2 in the tumor microenvironment

• Project/Area Number: 21K15508
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kumamoto University
• Principal Investigator: Horiguchi Haruki 熊本大学, 大学院生命科学研究部(医), 特任助教 (70755454)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: がん免疫 / ANGPTL2 / がん微小環境 / 抗腫瘍免疫

Outline of Research at the Start

がん病態においてがん細胞由来のアンジオポエチン様因子2(ANGPTL2)ががん細胞自身へのオートクリン作用によりがんの進展を促進することが解明されてきた。一方で、最近申請者は線維芽細胞由来のANGPTL2が樹状細胞やマクロファージを介した抗腫瘍免疫応答を誘導することでがんの進行を抑制することを報告した。本研究課題では、がん微小環境におけるANGPTL2のがん促進/抑制制御機構の理解に挑み、その成果ががん微小環境におけるがん細胞と間質細胞の相互作用の分子基盤解明につながり、様々ながんに対する個別化がん治療戦略確立への応用が期待される。

Outline of Final Research Achievements

The diversity of the cancer microenvironment is the greatest obstacle to the development of cancer therapies, and a complete understanding of the cancer microenvironment is essential for the development of innovative cancer therapies. Recently, it has been reported that ANGPTL2 has dual roles of cancer promotion and suppression, depending on the expressing and target cells. In this study, it was suggested that cancer cell-derived ANGPTL2 and fibroblast-derived ANGPTGL2 have different glycosylation, and that this difference determines the cancer-promoting and cancer-suppressing effects of ANGPTL2. In addition, it was suggested that the difference in carcinogenic context determined the priority of the cancer-promoting effect of cancer cell-derived ANGPTL2 and the cancer-suppressing effect of stroma-derived ANGPTL2.

Academic Significance and Societal Importance of the Research Achievements

これらの知見は、これまで明らかにされてこなかったがん微小環境の細胞間ネットワーク構築を担う分子群の理解に新たな視点を与えることが期待でき、一人ひとりの遺伝子発現、細胞構成に合わせたがん治療戦略の確立への応用が期待される。

Research Products

• [Journal Article] Tumor cell-derived ANGPTL2 promotes β-catenin-driven intestinal tumorigenesis. (2022)
  • Author(s): 1.Horiguchi H, Kadomatsu T, Yumoto S, Masuda T, Miyata K, Yamamura S, Sato M, Morinaga J, Ohtsuki S, Baba H, Moroishi T, and Oike Y
  • Journal Title: Oncogene Volume: 41 Issue: 33 Pages: 4208-4041
  • DOI: 10.1038/s41388-022-02405-8
  • Peer Reviewed
• [Journal Article] The lncRNA Caren antagonizes heart failure by inactivating DNA damage response and activating mitochondrial biogenesis (2021)
  • Author(s): Sato Michio, Kadomatsu Tsuyoshi, Miyata Keishi, Warren Junco S., Tian Zhe、Node Koichi、Araki Kimi、 Oike Yuichi et al
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 2529-2529
  • DOI: 10.1038/s41467-021-22735-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia (2021)
  • Author(s): Fukami Hirotaka、Morinaga Jun、Nakagami Hironori、Hayashi Hiroki、Okadome Yusuke、Matsunaga Eiji、Kadomatsu Tsuyoshi、Horiguchi Haruki、Sato Michio、Sugizaki Taichi、Kuwabara Takashige、Miyata Keishi、Mukoyama Masashi、Morishita Ryuichi、Oike Yuichi
  • Journal Title: Cell Reports Medicine Volume: 2 Issue: 11 Pages: 100446-100446
  • DOI: 10.1016/j.xcrm.2021.100446
  • Peer Reviewed / Open Access