Integrative analyses of lung adenocarcinomas that have undergone epithelial to mesenchymal transition (EMT) and those that retain an epithelial phenotype

• Project/Area Number: 15K08364
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: Sakuma Yuji 札幌医科大学, 医学部, 准教授 (10364514)
• Co-Investigator(Kenkyū-buntansha): 山口 美樹 札幌医科大学, 医学部, 助教 (10530454)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肺腺癌 / 上皮間葉移行 / EGFR / 薬剤耐性 / 肺胞上皮 / TTF-1 / 幹細胞 / EGFR遺伝子変異 / 分子標的治療

Outline of Final Research Achievements

EGFR-mutant lung adenocarcinomas depend on the kinase for survival. We have identified a new molecular mechanism that contributes to TKI resistance, and a previously unrecognized membranous molecule TKI-resistant cancer cells selectively express. (1) The EGFR mutant lung adenocarcinoma cell line, H1975, has a subset of cells that exhibits an EMT phenotype and can thrive in the presence of EGFR TKIs. These cells depend on the isomerase Pin1 for survival in vitro, unlike their parental cells. (2) A mesenchymal EGFR-independent subline derived from the EGFR mutant lung adenocarcinoma cell line, HCC827, expressed ACE2 to a greater extent than its parental cells. We also developed an anti-ACE2 mouse monoclonal antibody (mAb), termed H8R64, that was internalized by ACE2-expressing cells. If an antibody-drug conjugate consisting of a humanized mAb based on H8R64 and a potent anticancer drug were produced, it could be effective for the treatment of EGFR-mutant lung adenocarcinomas.

Research Products

• [Journal Article] Angiotensin-converting enzyme 2 is a potential therapeutic target for EGFR-mutant lung adenocarcinoma. (2017)
  • Author(s): Yamaguchi M, Hirai S, Sumi T, Tanaka Y, Tada M, Nishii Y, Hasegawa T, Uchida H, Yamada G, Watanabe A, Takahashi H, Sakuma Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 487(3) Issue: 3 Pages: 613-618
  • DOI: 10.1016/j.bbrc.2017.04.102
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial-mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis. (2017)
  • Author(s): Yamaguchi M, Hirai S, Tanaka Y, Sumi T, Miyajima M, Mishina T, Yamada G, Otsuka M, Hasegawa T, Kojima T, Niki T, Watanabe A, Takahashi H, Sakuma Y.
  • Journal Title: Lab Invest. Volume: Mar;97(3) Issue: 3 Pages: 232-242
  • DOI: 10.1038/labinvest.2016.135
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial-mesenchymal transition phenotype. (2016)
  • Author(s): Sakuma Y, Nishikiori H, Hirai S, Yamaguchi M, Yamada G, Watanabe A, Hasegawa T, Kojima T, Niki T, Takahashi H.
  • Journal Title: Lab Invest. Volume: 96 Issue: 4 Pages: 391-398
  • DOI: 10.1038/labinvest.2015.155
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] EGFR変異陽性肺腺癌と特発性肺線維症の分子細胞病理学 (2016)
  • Author(s): 佐久間裕司
  • Organizer: 第62回日本病理学会秋期特別総会
  • Place of Presentation: 金沢市文化ホール（石川県金沢市）
  • Year and Date: 2016-11-10
  • Invited
• [Presentation] Isomerase Pin1 promotes survival in EGFR mutant lung adenocarcinoma c ells with an EMT phenotype (2016)
  • Author(s): 佐久間裕司、長谷川 匡、仁木利郎
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（仙台市）
  • Year and Date: 2016-05-12
• [Remarks] 札幌医科大学医学部附属フロンティア医学研究所・分子医学部門
  • URL: http://web.sapmed.ac.jp/molm/
• [Remarks] 札幌医科大学医学部附属フロンティア医学研究所分子医学部門
  • URL: http://web.sapmed.ac.jp/molm/