The elucidation of mechanisms and the development of novel therapeutic methods for mutant p53-induced EMT in lung cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H03770
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Kyoto University
• Principal Investigator: MENJU Toshi 京都大学, 医学研究科, 准教授 (30527081)
• Co-Investigator(Kenkyū-buntansha): 佐藤 篤靖 京都大学, 医学研究科, 講師 (30706677)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 肺癌 / 上皮間葉転換 / 浸潤・転移 / EGFR変異 / p53変異 / 遺伝子改変マウス

Outline of Final Research Achievements

We confirmed the activation of EMT in lung cancer cell lines by p53 mutation and analyzed the differences by mutation type.We performed drug screening for compounds that inhibit TGFβ-induced EMT in the A549 lung cancer cell line, and we were able to select 7 drugs from approximately 2500 existing drugs and compounds, and several of them actually showed the inhibitory effect on EMT in lung cancer cell lines.
We generated genetically engineered mice by crossing EGFR mutant lung cancer mice with p53 mutant mice and found that p53 mutation yielded poorly differentiated tumors with solid components.Using the L-PDX method, we successfully transplanted human lung cancer into mice in 7 out of 9 resected specimens, and we developed a system for future studies to verify drug efficacy with PDX, which was published.

Free Research Field

呼吸器外科

Academic Significance and Societal Importance of the Research Achievements

p53遺伝子変異が肺癌に段階的なEMT活性化を誘導することを実験で示し、これらの細胞株やマウス腫瘍細胞の解析により、今後のさらなるメカニズムの解明に役立つと考えられた。またEMT活性化には可塑性が認められ、見出した薬剤によりEMT抑制のための新規開発の始原となることが期待できる。
また実験系として、EMT抑制のためのドラッグスクリーニング系の新規開発やヒト肺癌細胞のPDXによるex vivo実験を可能とするL-PDX法の開発に成功し、これを論文化して、広く社会に知らしめることで、浸潤転移を抑制する新規薬剤によるがん治療のパラダイムシフトを起こす可能性がある。