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

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

Genes Dis. 2019 Oct 29;8(2):203-214. doi: 10.1016/j.gendis.2019.10.012. eCollection 2021 Mar.

Authors

Kuei-Ling Tung^{1

2}, Kai-Yuan Chen^{2

3}, Marcos Negrete^{2

3}, Tianyi Chen², Alexias Safi^{3

4}, Abed Alhalim Aljamal⁵, Lingyun Song⁴, Gregory E Crawford^{3

4}, Shengli Ding², David S Hsu^{3

5}, Xiling Shen^{2

3

6}

Affiliations

¹ Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, 14853, USA.
² Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA.
³ Center for Genomics and Computational Biology, Duke University, Durham, NC, 27708, USA.
⁴ Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, 27708, USA.
⁵ Department of Medical Oncology, Duke University Medical Center, Durham, NC, 27708, USA.
⁶ Duke Cancer Institute, Duke University, Durham, NC, 27708, USA.

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.

Keywords: Chromatin accessibility; Drug screening; Patient-derived organoids; Personalized medicine; Target discovery.

Abstract

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