The elucidation of key signaling pathways and the establishment of treatment strategies for mutant p53-induced epithelio-mesenchymal transition in lung cancer

• Project/Area Number: 18K19578
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Kyoto University
• Principal Investigator: Date Hiroshi 京都大学, 医学研究科, 教授 (60252962)
• Co-Investigator(Kenkyū-buntansha): 園部 誠 京都大学, 医学研究科, 准教授 (00432378) ; 毛受 暁史 京都大学, 医学研究科, 講師 (30527081)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
• Keywords: p53 / 肺癌 / 上皮間葉転換（EMT） / EGFR / スタチン / 変異型p53遺伝子 / 浸潤転移 / 上皮間葉転換（EMT / 変異型p５３ / 上皮間葉転換 / シグナル経路 / 治療

Outline of Final Research Achievements

Stable expression cell lines were generated by transfection of wild-type and mutant p53 into lung cancer cell lines. Wild-type p53 cell lines expressed epithelial markers, but only mutant p53-expressing lines showed EMT changes to the mesenchymal type, showing increased invasive capacity and drug resistance. These changes were attenuated by statin administration, with recovery from mesenchymal to epithelial form.
In a study using clinical specimens, 239 completely resected cases of lung adenocarcinoma were analyzed. All cases were stratified by p53 mutation status, and p53-mutant group showed enhanced EMT activity and poor prognosis. Furthermore, a subgroup analysis of the p53 mutant group with and without statins showed a better prognosis in the statin-treated group.

Academic Significance and Societal Importance of the Research Achievements

現在、浸潤転移能を直接標的とする治療法はまだない。本研究の学術的意義は、変異型p53という肺癌の50%を占める腫瘍特異的な変化による浸潤転移能に関するEMTを標的としている点である。スタチンという既存薬によるEMTの回復が可能であり、臨床応用へのハードルも低い。また分子標的薬使用中のEMTによる薬剤耐性化が問題となっているが、これを克服することで、既存の分子標的治療薬との相乗効果も考えられる。
結果、術後再発予防や、遠隔転移症例に対する局所療法の適応拡大など様々な点で、既存治療法に加えて新たな癌治療戦略を採ることが可能となり、癌治療のパラダイムシフトにつながりうる。

Research Products

• [Journal Article] Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection (2019)
  • Author(s): Nishikawa Shigeto、Menju Toshi、Takahashi Koji、Miyata Ryo、Chen Yoshikawa Toyofumi Fengshi、Sonobe Makoto、Yoshizawa Akihiko、Sabe Hisataka、Sato Tosiya、Date Hiroshi
  • Journal Title: Cancer Management and Research Volume: Volume 11 Pages: 3419-3432
  • DOI: 10.2147/cmar.s200819
  • Peer Reviewed / Open Access
• [Journal Article] The Ratios of monounsaturated to saturated phosphatidylcholines in lung adenocarcinoma microenvironment analyzed by Liquid Chromatography-Mass spectrometry and imaging Mass spectrometry. (2019)
  • Author(s): Muranishi, Y., T. Sato, S. Ito, J. Satoh, A. Yoshizawa, S. Tamari, Y. Ueda, Y. Yutaka, T. Menju, T. Nakamura and H. Date
  • Journal Title: Scientific Reports Volume: 1 Issue: 1 Pages: 8916-8916
  • DOI: 10.1038/s41598-019-45506-3
  • NAID: 120006777029
  • Peer Reviewed
• [Journal Article] Prognostic Significance of Phosphorylated Fyn in Patients with Lung Adenocarcinoma after Lung Resection. (2019)
  • Author(s): Nishikawa, S., T. Menju, K. Takahashi, R. Miyata, M. Sonobe, A. Yoshizawa and H. Date
  • Journal Title: Annals of Thoracic Cardiovascular Surgery Volume: 5 Pages: 246-252
  • NAID: 130007731493
  • Peer Reviewed
• [Journal Article] Prognostic impact of microscopic vessel invasion and visceral pleural invasion and their correlations with epithelial-mesenchymal transition, cancer stemness, and treatment failure in lung adenocarcinoma. (2019)
  • Author(s): Neri, S., T. Menju, T. Sowa, Y. Yutaka, D. Nakajima, M. Hamaji, A. Ohsumi, T. F. Chen-Yoshikawa, T. Sato, M. Sonobe, A. Yoshizawa, H. Haga and H. Date
  • Journal Title: Lung Cancer Volume: 128 Pages: 13-19
  • DOI: 10.1016/j.lungcan.2018.12.001
  • Peer Reviewed
• [Presentation] 上皮間葉転換を標的とした肺癌新規治療法の開発 (2019)
  • Author(s): 毛受暁史、西川滋人、曽和晃正２、千葉直久、宮本英明、玉里滋幸、野口未紗、石川浩之、宮田亮、伊達洋至
  • Organizer: 第60回日本肺癌学会学術集会
• [Presentation] 上皮間葉転換を標的とした肺癌新規治療法の開発 (2019)
  • Author(s): 毛受暁史、西川滋人、曽和晃正、玉里滋幸、野口未紗、石川浩之、宮田亮、田中里奈、山田義人、豊洋次郎、中島大輔、大角明宏、濱路政嗣、佐藤寿彦、陳豊史、伊達洋至
  • Organizer: 第72回日本胸部外科学会定期学術集会
• [Presentation] Arf6-related Invasive Pathway Deteriorated Patients’ Prognosis in Mutant EGFR Lung Adenocarcinoma (2019)
  • Author(s): Toshi Menju, Misa Noguchi, Shigeyuki Tamari, Hiroyuki Ishikawa, Ryo Miyata, Koji Takahashi, Shigeto Nishikawa, Satona Tanaka, Yoshito Yamada, Yojiro Yutaka, Daisuke Nakajima, Fengshi-Toyofumi Chen-Yoshikawa, Toshihiko Sato, Hiroshi Date
  • Organizer: WCLC2019
  • Int'l Joint Research
• [Presentation] Suppression of mutant-p53-induced EMT by statins have double-edged effects on the patients with lung adenocarcinoma according to p53 mutation status (2019)
  • Author(s): S.Nishikawa, T.Menju, T.Sowa, K.Takahashi, R.Miyata, H.Ishikawa, D.Nakajima, M.Hamaji, H.Motoyama, A.Aoyama, T.sato, F.Chen-Yoshikawa, M.Sonobe, H.Date
  • Organizer: American Association for Cancer Research, Annual Meeting
  • Int'l Joint Research