Basic research for the development of personalized therapeutic strategies against a rare renal cell carcinoma

• Project/Area Number: 18K07236
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kumamoto University
• Principal Investigator: KADOMATSU Tsuyoshi 熊本大学, 大学院生命科学研究部(医), 講師 (90555757)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 腎細胞がん / ANGPTL2 / 尿中バイオマーカー / miRNA / がん免疫 / TFE3融合遺伝子 / 転座型腎細胞がん / 稀少腎細胞がん

Outline of Final Research Achievements

In this study, we challenged to identify urinary biomarkers for early diagnosis of Xp11.2 translocation renal cell carcinoma (tRCC) and examined molecular mechanisms underlying the development and progression of Xp11.2 translocation renal cell carcinoma. Our results showed that miR-204-5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11.2 tRCC. We also demonstrated that tumor cell-derived ANGPTL2 accelerates the progression of Xp11.2 tRCC, suggesting that ANGPTL2 signaling could be a novel therapeutic target. Moreover, we showed that tumor stroma-derived ANGPTL2 suppresses tumor progression by facilitating the activation of anti-tumor immune responses.

Academic Significance and Societal Importance of the Research Achievements

本研究では、稀少がんであるが故に治療法や診断マーカーの研究開発が困難なXp11.2転座型腎細胞がんについて、そのモデルマウスを独自に開発し、早期診断に利用可能な新規バイオマーカーや新規治療標的分子を解明するなど、その成果はXp11.2転座型腎細胞がんの個別化治療戦略の確立に寄与するものである。さらに、本研究の成果は、ANGPTL2シグナルを介した抗腫瘍免疫応答制御の解明といった学術的意義も有する。

Research Products

• [Int'l Joint Research] NIH(米国)
• [Journal Article] Stroma-derived ANGPTL2 establishes an anti-tumor microenvironment during intestinal tumorigenesis (2020)
  • Author(s): Horiguchi Haruki、Kadomatsu Tsuyoshi、Miyata Keishi、Terada Kazutoyo、Sato Michio、Torigoe Daisuke、Morinaga Jun、Moroishi Toshiro、Oike Yuichi
  • Journal Title: Oncogene Volume: 40 Issue: 1 Pages: 55-67
  • DOI: 10.1038/s41388-020-01505-7
  • Peer Reviewed
• [Journal Article] Serum anti-p53 autoantibodies in angiosarcoma. (2020)
  • Author(s): Mihoko Kiyohara , Jun Aoi , Ikko Kajihara , Saki Otuka , Tuyoshi Kadomatsu , Satoshi Fukushima , Hironobu Ihn
  • Journal Title: Journal of Dermatology Volume: 47 Issue: 8 Pages: 849-854
  • DOI: 10.1111/1346-8138.15416
  • Peer Reviewed / Open Access
• [Journal Article] Tumor cell-derived angiopoietin-like protein 2 establishes a preference for glycolytic metabolism in lung cancer cells. (2020)
  • Author(s): Osumi H, Horiguchi H, Kadomatsu T, Tashiro K, Morinaga J, Takahashi T, Ikeda K, Ito T, Suzuki M, Endo M, Oike Y
  • Journal Title: Cancer Sci Volume: - Issue: 4 Pages: 1241-1253
  • DOI: 10.1111/cas.14337
  • Peer Reviewed / Open Access
• [Journal Article] Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity. (2019)
  • Author(s): Horiguchi H, Kadomatsu T, Kurahashi R, Hara C, Miyata K, Baba M, Osumi H, Terada K, Araki K, Takai T, Kamba T, Linehan WM, Moroishi T, Oike Y.
  • Journal Title: Genes Dev Volume: 33 Issue: 23-24 Pages: 1641-1656
  • DOI: 10.1101/gad.329417.119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MiR-204-5p: a novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma. (2019)
  • Author(s): Kurahashi R, Kadomatsu T, Baba M, Hara C, Itoh H, Miyata K, Endo M, Morinaga J, Terada K, Araki K, Eto M, Schmidt LS, Kamba T, Linehan WM, Oike Y.
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 6 Pages: 1897-1908
  • DOI: 10.1111/cas.14026
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TFE3 Xp11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease. (2019)
  • Author(s): Baba M, Furuya M, Motoshima T, Lang M, Funasaki S, Ma W, Sun HW, Hasumi H, Huang Y, Kato I, Kadomatsu T, Satou Y, Morris N, Karim BO, Ileva L, Kalen JD, Wilan Krisna LA, Hasumi Y, Sugiyama A, Kurahashi R, Nishimoto K, Oyama M, Nagashima Y, Kuroda N, Araki K, Eto M, Yao M, Kamba T, Suda T, Oike Y, Schmidt LS, Linehan WM
  • Journal Title: Molecular Cancer Research Volume: 印刷中 Issue: 8 Pages: 1613-1626
  • DOI: 10.1158/1541-7786.mcr-18-1235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of angiopoietin-like proteins in regulation of stem cell activity. (2019)
  • Author(s): Kadomatsu T, Oike Y.
  • Journal Title: J. Biochem. Volume: 165 Issue: 4 Pages: 309-315
  • DOI: 10.1093/jb/mvz005
  • Peer Reviewed / Open Access
• [Presentation] Intercellular communication via angiopoietin-like protein 2 signaling in the regulation of anti-tumor immunity (2020)
  • Author(s): Tsuyoshi Kadomatsu, Haruki Horiguchi, Yuichi Oike
  • Organizer: 第43回日本分子生物学会年会
  • Invited
• [Presentation] 加齢関連疾患とアンジオポエチン様因子2シグナル (2019)
  • Author(s): 門松 毅
  • Organizer: 第19回日本抗加齢医学会総会
  • Invited
• [Presentation] アンジオポエチン様因子2シグナルによる代謝制御変容と加齢関連疾患 (2019)
  • Author(s): 門松 毅
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] 加齢関連疾患の発症・進展とアンジオポエチン様因子2シグナル (2019)
  • Author(s): 門松 毅，尾池雄一
  • Organizer: 第91回日本生化学会大会
  • Invited
• [Presentation] アンジオポエチン様因子2シグナルによる加齢関連疾患の発症・進展の分子機構 (2019)
  • Author(s): 門松 毅，尾池雄一
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Book] アンチ・エイジング医学 特集 老化と炎症 5. 慢性炎症とサルコペニア (2019)
  • Author(s): 門松 毅
  • Total Pages: 115
  • Publisher: メディカルレビュー社
• [Remarks] 熊本大学 大学院生命科学研究部 分子遺伝学講座
  • URL: http://www.kumamoto-u-molgene.jp
• [Remarks] 熊本大学 大学院生命科学研究部 分子遺伝学講座
  • URL: http://www.kumamoto-u-molgene.jp