2022 Fiscal Year Final Research Report

Development of cancer stem cell specific miRNA delivery system for recurrence and metastasis from cancer by outer membrane vesicles of bacteria. .

Research Project

PDF

Project/Area Number	20K08943
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 55010:General surgery and pediatric surgery-related
Research Institution	Tokyo Medical University
Principal Investigator	Ueda Shinobu 東京医科大学, 医学部, 助手 (00521874)
Co-Investigator(Kenkyū-buntansha)	高梨正勝東京医科大学, 医学部, 講師 (80312007) 須藤カツ子東京医科大学, 医学部, 兼任講師 (50126091) 黒田雅彦東京医科大学, 医学部, 主任教授 (80251304) 土田明彦東京医科大学, 医学部, 兼任教授 (50207396)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	がん幹細胞 / 外膜小胞 / 核酸デリバリー
Outline of Final Research Achievements	In patients with breast cancer, primary chemotherapy often fails due to survival of chemoresistant breast cancer stem cells (BCSCs) which results in recurrence and metastasis of the tumor. Current hypotheses suggest that these recurrence and metastases arise from residual disseminated tumor cells (DTCs), which disseminate from primary lesions, undergoing an extended period of dormancy in the stroma of　metastasized organs. We profiled a series of differentially expressed membrane proteins between paternal adherent breast cancer cells and BCSC-mimicking mammosphere-derived cancer cells. In the mammosphere, we found that hsa-miR-27a were downregulated and TMEM59 was specifically upregulated. These results provide us novel molecular targets for BCSCs and can be a potential therapeutic modality for breast cancer. In this study, we engineered TMEM59 binding protein extracellular vesicles that specifically delivered miR-27a to DTCs.
Free Research Field	核酸治療
Academic Significance and Societal Importance of the Research Achievements	現在の核酸デリバリー法ではがん幹細胞への特異性は低く、その効果も少ない。近年、細菌が放出する外膜小胞 (outer membrane vesicles, OMV)ががんを縮小したという報告が注目されている。OMVは遺伝子の伝搬や細胞間輸送に関与していることが明らかになっており、ドラッグデリバリーシステムへの応用が期待されている。本研究では拒絶反応や細菌由来の毒性を軽減する目的で、乳酸菌 (L. acidophilus) のOMVを用いることとした。全身に散在し潜伏するがん幹細胞を標的とし、がんの根治を目指す。その結果、核酸医薬としての実用化への発展、臨床への応用が十分に期待できる。