Mandatory autophagy induction targeting gastric cancer stem cells by hybrid small molecule antibodies

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05291
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: SUZUKI HIDEKAZU 慶應義塾大学, 医学部(信濃町), 教授 (70255454)
• Co-Investigator(Kenkyū-buntansha): 津川 仁 慶應義塾大学, 医学部(信濃町), 講師 (30468483) ; 土居 信英 慶應義塾大学, 理工学部(矢上), 教授 (50327673)
• Research Collaborator: SAYA Hideyuki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 癌幹細胞 / H. pylori / オートファジー / CD44v9 / CAPZA1 / 一本鎖抗 / 膜透過促進ペプチド

Outline of Final Research Achievements

Although autophagy expression in H. pylori-infected cells is responsible for oncogenic CagA degradation and suppresses tumorigenesis, CD44v9-expressing cancer stem-like cells do not evoke autophagy and intracellular CagA accumulates. LAMP1-dependent autophagosome formation is also essential for CagA degrading autophagy, and we showed that CAPZA1 would bind to LRP1-ICD in the nucleus and inhibit LAMP1 expression, and when CAPZA1 is loaded on CAPZA1 overexpressing cells, CD44v9 expression was enhanced. In order to target CD44v9 and a large amount of CAPZA1 translocated to the nucleus, it was possible to release from intracellular foreign body degradation by combining TAT with human Syncytin 1-derived membrane-penetrating peptide S19. A large amount of protein was purified by fusing the created anti-CD44v9 single-chain antibody and a human-derived membrane-penetrating peptide, and CD44v9-positive cell selective cellular uptake was confirmed.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

癌幹細胞標的療法は治療抵抗性癌を根本的に克服する革新的癌治療戦略として大いに期待される。これまで、癌幹細胞の発生起源は明確にされていなかったが、代表者らは、最近、CAPZA1過剰発現細胞が癌幹細胞の前駆責任細胞であることを報告した(Autophagy 2019)。そこで、本研究では、CAPZA1を標的し、胃癌幹細胞の発生を抑制し、かつ治療する技術を開発した。これまでの癌幹細胞を標的する癌治療戦略では、常に、分子標的マテリアルの開発に難航してきたが、本研究では、独自のmRNAディスプレイ法や膜透過促進ペプチドを駆使することでCAPZA1を標的するマテリアルを開発しえた。