https://scholars.lib.ntu.edu.tw/handle/123456789/587227
標題: | Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts | 作者: | Lee P.-J. CHAO-CHI HO Ho H. Chen W.-J. Lin C.-H. Lai Y.-H. Juan Y.-C. Chu W.-C. Lee J.-H. SHENG-FANG SU Chen H.-Y. Chen J.J.W. Chang G.-C. Li K.-C. PAN-CHYR YANG HUEI-WEN CHEN |
公開日期: | 2021 | 出版社: | Ivyspring International Publisher | 卷: | 11 | 期: | 19 | 起(迄)頁: | 9667-9686 | 來源出版物: | Theranostics | 摘要: | The tumorous niche may drive the plasticity of heterogeneity and cancer stemness, leading to drug resistance and metastasis, which is the main reason of treatment failure in most cancer patients. The aim of this study was to establish a tumor microenvironment (TME)-based screening to identify drugs that can specifically target cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs) in the TME. Methods: Lung cancer patient-derived cancer cell and CAFs were utilized to mimic the TME and reproduce the stemness properties of CSCs in vitro and develop a high-throughput drug screening platform with phenotypical parameters. Limiting dilution assay, sphere-forming and ALDH activity assay were utilized to measure the cancer stemness characteristics. In vivo patient-derived xenograft (PDX) models and single-cell RNA sequencing were used to evaluate the mechanisms of the compounds in CSCs and CAFs. Results: The TME-based drug screening platform could comprehensively evaluate the response of cancer cells, CSCs and CAFs to different treatments. Among the 1,524 compounds tested, several drugs were identified to have anti-CAFs, anticancer and anti-CSCs activities. Aloe-emodin and digoxin both show anticancer and anti-CSCs activity in vitro and in vivo, which was further confirmed in the lung cancer PDX model. The combination of digoxin and chemotherapy improved therapeutic efficacy. The single-cell transcriptomics analysis revealed that digoxin could suppress the CSCs subpopulation in CAFs-cocultured cancer cells and cytokine production in CAFs. Conclusions: The TME-based drug screening platform provides a tool to identify and repurpose compounds targeting cancer cells, CSCs and CAFs, which may accelerate drug development and therapeutic application for lung cancer patients. ? The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85117295857&doi=10.7150%2fTHNO.62676&partnerID=40&md5=bb750fac7c84ea18dda4b6cc1eb4798f https://scholars.lib.ntu.edu.tw/handle/123456789/587227 |
ISSN: | 1838-7640 | DOI: | 10.7150/THNO.62676 |
顯示於: | 腫瘤醫學研究所 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。