Development of therapeutics for lung cancer that target factors stabilizing epithelial-to-mesenchymal transition

• Project/Area Number: 19K22617
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Nagoya University
• Principal Investigator: Sato Mitsuo 名古屋大学, 医学系研究科(保健), 教授 (70467281)
• Co-Investigator(Kenkyū-buntansha): 長谷 哲成 名古屋大学, 医学部附属病院, 助教 (30621635) ; 湯川 博 名古屋大学, 未来社会創造機構, 招へい教員 (30634646) ; 田中 一大 名古屋大学, 医学部附属病院, 病院助教 (40809810) ; 川井 久美 名古屋大学, 医学系研究科(保健), 准教授 (50362231) ; 川口 晃司 名古屋大学, 医学部附属病院, 病院准教授 (10402611)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 上皮間葉細胞転換 / 肺癌 / 創薬

Outline of Research at the Start

上皮間葉細胞転換（EMT）は癌細胞が上皮系から間葉系へ転換し悪性度を増強する現象である。これまではEMTを完了した細胞の悪性度が最も高いとされてきた。しかし、応募者の準備データは部分的なEMT細胞の方が完全なEMT細胞に比べ悪性形質が高いことを示唆する。また、部分的EMTを安定化する未知の因子の存在が推測され、これは癌の悪性形質を決定する有望な治療標的の可能性がある。以上より、本研究は肺癌治療標的として期待される部分的EMTの“安定化因子”の発見およびそれらを標的とする創薬を目的とする。方法として、応募者開発の正常気管支上皮細胞モデル（HBEC）を用いた機能的なスクリーニングなどを実施する。

Outline of Final Research Achievements

Epithelial to mesenchymal transition (EMT) is a phenomenon where cancer cells convert from the epithelial to the mesenchymal cells, leading to enhanced the malignancy. The purpose of this study was to elucidate the role of the GRHL2 gene, which is known as an EMT inhibitor and stabilizer. GRHL2 expression correlates with the epithelial properties of lung cancer cells and is highly expressed in tumor tissues of adenocarcinoma and squamous cell carcinoma compared to normal lung tissue. GRHL2 knockdown by RNA interference in lung cancer cell lines and immortalized normal bronchial epithelial cell lines resulted in promotion and suppression of proliferation. These results suggest that GRHL2 functions as an EMT inhibitor but also has a cancer-promoting effect.

Academic Significance and Societal Importance of the Research Achievements

上皮間葉細胞転換（epithelial to mesenchymal transition, EMT）は癌細胞が上皮系から間葉系へ転換し悪性度を増強する現象である。EMTの制御による癌治療の実現にはEMTのさらなる機序解明が必要である。本課題はEMT抑制遺伝子として知られるGRHL2がEMT抑制因子として機能するにもかかわらず癌促進的な作用も併せ持つことを示した。EMTの機序解明における新たな知見を提供した。

Research Products

• [Int'l Joint Research] テキサス大学サウスウエスタンメディカルセンター(米国)
• [Journal Article] Resistance to mutant KRAS V12-induced senescence in an hTERT/Cdk4-immortalized normal human bronchial epithelial cell line (2022)
  • Author(s): Muraki N, Yamada M, Doki H, Nakai R, Komeda K, Goto D, Kawabe N, Matsuoka K, Matsushima M, Kawabe T, Tanaka I, Morise M, Shay JW, Minna JD, Sato M.
  • Journal Title: Exp Cell Res . Volume: 414 Issue: 1 Pages: 113053-113053
  • DOI: 10.1016/j.yexcr.2022.113053
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Oxytocin receptor is a promising therapeutic target of malignant mesothelioma (2021)
  • Author(s): Oxytocin receptor is a promising therapeutic target of malignant mesothelioma. Kodama Y, Tanaka I, Sato T, Hori K, Gen S, Morise M, Matsubara D, Sato M, Sekido Y, Hashimoto N.
  • Journal Title: Cancer science Volume: 112 Issue: 9 Pages: 3520-3532
  • DOI: 10.1111/cas.15025
  • Peer Reviewed / Open Access
• [Journal Article] Spatiotemporal depletion of tumor-associated immune checkpoint PD-L1 with near-infrared photoimmunotherapy promotes antitumor immunity (2021)
  • Author(s): Shunichi Taki, Kohei Matsuoka, Yuko Nishinaga, Kazuomi Takahashi, Hirotoshi Yasui, Chiaki Koike, Misae Shimizu , Mitsuo Sato , Kazuhide Sato
  • Journal Title: J Immunother Cancer . Volume: 9 Issue: 11 Pages: e003036-e003036
  • DOI: 10.1136/jitc-2021-003036
  • Peer Reviewed / Open Access
• [Journal Article] Immortalized normal human lung epithelial cell models for studying lung cancer biology (2020)
  • Author(s): Sato M, Shay JW, Minna JD.
  • Journal Title: Respir Investig . Volume: 58(5) Pages: 344-354
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chemotherapy Induced Changes to Fibrin Clots Properties in Lung Cancer: Is It Favorable? (2019)
  • Author(s): Sato M.
  • Journal Title: J Thorac Dis Volume: 11(Suppl 9) Issue: S9 Pages: S1126-S1128
  • DOI: 10.21037/jtd.2019.04.103
  • Peer Reviewed / Open Access
• [Presentation] An hTERT/CDK4-immortalized normal human bronchial epithelial cell line is highly resistant to mutant KRAS-induced senescence (2021)
  • Author(s): Nao Muraki, Hinako Doki, Riho Nakai, Mizuki Yamada, Kazuki Komeda, Nozomi Kawabe, Kouhei Matsuoka, Miyoko Matsushima, Tsutomu Kawabe, Ichidai Tanaka, Masahiro Morise and Mitsuo Sato
  • Organizer: The 25th Congress of the Asian Pacific Society of Respirology (APSR 2021)
  • Int'l Joint Research
• [Presentation] UHRF1, a regulator of methylation, as a diagnostic and prognostic marker for lung cancer (2020)
  • Author(s): 佐藤 光夫、後藤 大輝、上床 菜月、中嶋 萌夏、小池 眞由、川合 花穂、米田一樹、小玉 勇太、宮沢 亜矢子、田中一大、長谷 哲成、森瀬 昌宏、関戸 好孝、川部 勤、 長谷川 好規
  • Organizer: 第60回日本呼吸器学会学術講演会