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

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

doi:10.1016/j.gendis.2019.10.012

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

更新时间：2022-06-24

- Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance
- Genes & Diseases Vol. 8, Issue 2, (2021)
- 作者机构：
  
  1. Department of Biological and Environmental Engineering, Cornell University, Ithaca,NY,USA,14853
  2. Department of Biomedical Engineering, Pratt School of Engineering, Duke University,NC,Durham,USA,27708
  3. Center for Genomics and Computational Biology, Duke University,NC,Durham,USA,27708
  4. Department of Pediatrics, Division of Medical Genetics, Duke University,NC,Durham,USA,27708
  5. Department of Medical Oncology, Duke University Medical Center,NC,Durham,USA,27708
  6. Duke Cancer Institute, Duke University,NC,Durham,USA,27708
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2019.10.012
  CLC：
- Published：2021，
  
  Published Online：1 March 2021，
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Kuei-Ling Tung, Kai-Yuan Chen, Marcos Negrete, et al. Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance. [J]. Genes & Diseases 8(2).(2021)
DOI：

Kuei-Ling Tung, Kai-Yuan Chen, Marcos Negrete, et al. Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance. [J]. Genes & Diseases 8(2).(2021) DOI： 10.1016/j.gendis.2019.10.012.

摘要

Abstract

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.

关键词

Keywords

Chromatin accessibilityDrug screeningPatient-derived organoidsPersonalized medicineTarget discovery

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