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Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts
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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490509/ https://www.ncbi.nlm.nih.gov/pubmed/34646392 http://dx.doi.org/10.7150/thno.62676 |
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author | Lee, Pei-Jung Ho, Chao-Chi Ho, Hao Chen, Wan-Jiun Lin, Chiu-Hua Lai, Yi-Hua Juan, Yi-Chen Chu, Wen-Chung Lee, Jia-Hua Su, Sheng-Fang Chen, Hsuan-Yu Chen, Jeremy J. W. Chang, Gee-Chen Li, Ker-Chau Yang, Pan-Chyr Chen, Huei-Wen |
author_facet | Lee, Pei-Jung Ho, Chao-Chi Ho, Hao Chen, Wan-Jiun Lin, Chiu-Hua Lai, Yi-Hua Juan, Yi-Chen Chu, Wen-Chung Lee, Jia-Hua Su, Sheng-Fang Chen, Hsuan-Yu Chen, Jeremy J. W. Chang, Gee-Chen Li, Ker-Chau Yang, Pan-Chyr Chen, Huei-Wen |
author_sort | Lee, Pei-Jung |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8490509 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-84905092021-10-12 Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts Lee, Pei-Jung Ho, Chao-Chi Ho, Hao Chen, Wan-Jiun Lin, Chiu-Hua Lai, Yi-Hua Juan, Yi-Chen Chu, Wen-Chung Lee, Jia-Hua Su, Sheng-Fang Chen, Hsuan-Yu Chen, Jeremy J. W. Chang, Gee-Chen Li, Ker-Chau Yang, Pan-Chyr Chen, Huei-Wen Theranostics Research Paper 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. Ivyspring International Publisher 2021-09-21 /pmc/articles/PMC8490509/ /pubmed/34646392 http://dx.doi.org/10.7150/thno.62676 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/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. |
spellingShingle | Research Paper Lee, Pei-Jung Ho, Chao-Chi Ho, Hao Chen, Wan-Jiun Lin, Chiu-Hua Lai, Yi-Hua Juan, Yi-Chen Chu, Wen-Chung Lee, Jia-Hua Su, Sheng-Fang Chen, Hsuan-Yu Chen, Jeremy J. W. Chang, Gee-Chen Li, Ker-Chau Yang, Pan-Chyr Chen, Huei-Wen Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts |
title | Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts |
title_full | Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts |
title_fullStr | Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts |
title_full_unstemmed | Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts |
title_short | Tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts |
title_sort | tumor microenvironment-based screening repurposes drugs targeting cancer stem cells and cancer-associated fibroblasts |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490509/ https://www.ncbi.nlm.nih.gov/pubmed/34646392 http://dx.doi.org/10.7150/thno.62676 |
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