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

Genes and Diseases

Tianyi Chen¹  Abed Alhalim Aljamal¹  Kai-Yuan Chen²  Shengli Ding³  Gregory E. Crawford⁴  Kuei-Ling Tung⁵  Alexias Safi⁶  Lingyun Song⁶  Marcos Negrete⁶  David S. Hsu⁷  Xiling Shen⁸ 

[1] Center for Genomics and Computational Biology, Duke University, Durham, NC, 27708, USA;Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA;Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, 27708, USA;Center for Genomics and Computational Biology, Duke University, Durham, NC, 27708, USA;Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, 14853, USA;Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA;Department of Medical Oncology, Duke University Medical Center, Durham, NC, 27708, USA;Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, 27708, USA;

关键词: Chromatin accessibility;    Drug screening;    Patient-derived organoids;    Personalized medicine;    Target discovery;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown