Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance.
Chromatin accessibility
Drug screening
Patient-derived organoids
Personalized medicine
Target discovery
Journal
Genes & diseases
ISSN: 2352-3042
Titre abrégé: Genes Dis
Pays: Netherlands
ID NLM: 101635967
Informations de publication
Date de publication:
Mar 2021
Mar 2021
Historique:
received:
28
08
2019
revised:
20
10
2019
accepted:
21
10
2019
entrez:
17
5
2021
pubmed:
29
10
2019
medline:
29
10
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33997167
doi: 10.1016/j.gendis.2019.10.012
pii: S2352-3042(19)30099-6
pmc: PMC8099686
doi:
Types de publication
Journal Article
Langues
eng
Pagination
203-214Informations de copyright
© 2019 Chongqing Medical University. Production and hosting by Elsevier B.V.
Déclaration de conflit d'intérêts
The authors declare no potential conflicts of interest.
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