Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance

Colorectal cancer is a leading cause of cancer deaths. Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin chang...

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Main Authors:	Kuei-Ling Tung, Kai-Yuan Chen, Marcos Negrete, Tianyi Chen, Alexias Safi, Abed Alhalim Aljamal, Lingyun Song, Gregory E. Crawford, Shengli Ding, David S. Hsu, Xiling Shen
Format:	Article
Language:	English
Published:	Elsevier 2021-03-01
Series:	Genes and Diseases
Subjects:	Chromatin accessibility Drug screening Patient-derived organoids Personalized medicine Target discovery
Online Access:	http://www.sciencedirect.com/science/article/pii/S2352304219300996

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record_format	Article
spelling	doaj-cc3ad1c7ad58427e943bb6eceaf7cc902021-04-24T05:57:38ZengElsevierGenes and Diseases2352-30422021-03-0182203214Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistanceKuei-Ling Tung0Kai-Yuan Chen1Marcos Negrete2Tianyi Chen3Alexias Safi4Abed Alhalim Aljamal5Lingyun Song6Gregory E. Crawford7Shengli Ding8David S. Hsu9Xiling Shen10Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, 14853, USA; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USADepartment of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA; Center for Genomics and Computational Biology, Duke University, Durham, NC, 27708, USADepartment of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA; Center for Genomics and Computational Biology, Duke University, Durham, NC, 27708, USADepartment of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USACenter for Genomics and Computational Biology, Duke University, Durham, NC, 27708, USA; Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, 27708, USADepartment of Medical Oncology, Duke University Medical Center, Durham, NC, 27708, USADepartment of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, 27708, USACenter for Genomics and Computational Biology, Duke University, Durham, NC, 27708, USA; Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, 27708, USADepartment of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USACenter for Genomics and Computational Biology, Duke University, Durham, NC, 27708, USA; Department of Medical Oncology, Duke University Medical Center, Durham, NC, 27708, USADepartment of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA; Center for Genomics and Computational Biology, Duke University, Durham, NC, 27708, USA; Duke Cancer Institute, Duke University, Durham, NC, 27708, USA; Corresponding author.Colorectal cancer is a leading cause of cancer deaths. Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment. Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression. CRISPR/Cas9 silencing of fibroblast growth factor receptor 1 (FGFR1) and oxytocin receptor (OXTR) helped overcome oxaliplatin resistance. Similarly, treatment with oxaliplatin in combination with an FGFR1 inhibitor (PD166866) or an antagonist of OXTR (L-368,899) suppressed chemoresistant organoids. However, oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid, suggesting that chromatin accessibility changes are patient-specific. The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer.http://www.sciencedirect.com/science/article/pii/S2352304219300996Chromatin accessibilityDrug screeningPatient-derived organoidsPersonalized medicineTarget discovery
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Kuei-Ling Tung Kai-Yuan Chen Marcos Negrete Tianyi Chen Alexias Safi Abed Alhalim Aljamal Lingyun Song Gregory E. Crawford Shengli Ding David S. Hsu Xiling Shen
spellingShingle	Kuei-Ling Tung Kai-Yuan Chen Marcos Negrete Tianyi Chen Alexias Safi Abed Alhalim Aljamal Lingyun Song Gregory E. Crawford Shengli Ding David S. Hsu Xiling Shen Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance Genes and Diseases Chromatin accessibility Drug screening Patient-derived organoids Personalized medicine Target discovery
author_facet	Kuei-Ling Tung Kai-Yuan Chen Marcos Negrete Tianyi Chen Alexias Safi Abed Alhalim Aljamal Lingyun Song Gregory E. Crawford Shengli Ding David S. Hsu Xiling Shen
author_sort	Kuei-Ling Tung
title	Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance
title_short	Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance
title_full	Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance
title_fullStr	Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance
title_full_unstemmed	Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance
title_sort	integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance
publisher	Elsevier
series	Genes and Diseases
issn	2352-3042
publishDate	2021-03-01
description	Colorectal cancer is a leading cause of cancer deaths. Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment. Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression. CRISPR/Cas9 silencing of fibroblast growth factor receptor 1 (FGFR1) and oxytocin receptor (OXTR) helped overcome oxaliplatin resistance. Similarly, treatment with oxaliplatin in combination with an FGFR1 inhibitor (PD166866) or an antagonist of OXTR (L-368,899) suppressed chemoresistant organoids. However, oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid, suggesting that chromatin accessibility changes are patient-specific. The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer.
topic	Chromatin accessibility Drug screening Patient-derived organoids Personalized medicine Target discovery
url	http://www.sciencedirect.com/science/article/pii/S2352304219300996
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Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance

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