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
Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death in the United States.Three quarters of patients diagnosed with colorectal cancer will have early stage disease and...Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death in the United States.Three quarters of patients diagnosed with colorectal cancer will have early stage disease and despite surgical resection for curative intent,approximately 20%-25%of patients will recur with their disease within five years.The other 25%will present with advanced or metastatic disease and clinicians are faced with the challenge of choosing the most appropriate therapy for individual patients.Despite multiple treatment options which are now available and concomitant improvements in survival,advanced colorectal cancer remains universally fatal.The challenge for clinicians is to identify prognostic and predictive biomarkers that can assist in tailoring available treatments for an individual patient to improve clinical outcomes.This review will summarize current and future biomarkers in colorectal cancer and discuss their utility in managing patient care.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.
文摘Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death in the United States.Three quarters of patients diagnosed with colorectal cancer will have early stage disease and despite surgical resection for curative intent,approximately 20%-25%of patients will recur with their disease within five years.The other 25%will present with advanced or metastatic disease and clinicians are faced with the challenge of choosing the most appropriate therapy for individual patients.Despite multiple treatment options which are now available and concomitant improvements in survival,advanced colorectal cancer remains universally fatal.The challenge for clinicians is to identify prognostic and predictive biomarkers that can assist in tailoring available treatments for an individual patient to improve clinical outcomes.This review will summarize current and future biomarkers in colorectal cancer and discuss their utility in managing patient care.
