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 organoi...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.展开更多
基金WethankDukeCenterforGenomicandComputational Biology sequencingcorefacilityforresearchsupport.This work wassupportedbyNIHNCIU01CA217514andU01 CA214300.
文摘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.
