Precision medicine has shed new light on the treatment of heterogeneous cancer patients.However,intratumor heterogeneity strongly constrains the clinical benefit of precision medicine.Thus,rethinking therapeutic strat...Precision medicine has shed new light on the treatment of heterogeneous cancer patients.However,intratumor heterogeneity strongly constrains the clinical benefit of precision medicine.Thus,rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions,but also provide an avenue for precision medicine.Here,we explore the current approaches for targeting intratumor hetero-geneity and their limitations.Furthermore,we propose a theoretical strategy with a“homogenization”feature based on iatrogenic evolutionary selection to target intratumor heterogeneity.展开更多
Background:Breast cancer stem cells(BCSCs)are considered responsible for cancer relapse and drug resistance.Understanding the identity of BCSCs may open new avenues in breast cancer therapy.Although several discoverie...Background:Breast cancer stem cells(BCSCs)are considered responsible for cancer relapse and drug resistance.Understanding the identity of BCSCs may open new avenues in breast cancer therapy.Although several discoveries have been made on BCSC characterization,the factors critical to the origination of BCSCs are largely unclear.This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs.Methods:We detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency,and then performed target deep DNA sequencing at bulk-cell and single-cell levels.To identify the transcriptional program associated with BCSCs,bulk-cell and single-cell RNA sequencing was performed.Results:By using whole-genome sequencing of bulk cells,potential BCSC phenotype-associated mutation hotspot regions were detected.Validation by target deep DNA sequencing,at both bulk-cell and single-cell levels,revealed no genetic changes specifically associated with BCSC phenotype.Moreover,single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features.Notably,this transcriptomic variability was enriched during the transcription of 74 genes,revealed as BCSC markers.Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse,thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers.Conclusions:Transcriptomic variability,not genetic mutations,distinguishes BCSCs from non-BCSCs.The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.展开更多
基金supported by Innovative Research Team in University of Ministry of Education of China(No.IRT_17R15)National Natural Science Foundation of China(No.81630005 to QL,No.81573025 to QL)+1 种基金Dalian high-level talent innovation program(2016RD12 to QL)International scientific and technological cooperation of Dalian(2015F11GH095 to QL).
文摘Precision medicine has shed new light on the treatment of heterogeneous cancer patients.However,intratumor heterogeneity strongly constrains the clinical benefit of precision medicine.Thus,rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions,but also provide an avenue for precision medicine.Here,we explore the current approaches for targeting intratumor hetero-geneity and their limitations.Furthermore,we propose a theoretical strategy with a“homogenization”feature based on iatrogenic evolutionary selection to target intratumor heterogeneity.
基金supported by Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China(No.IRT_17R15)National Natural Science Foundation of China(Nos.81630005 to QL,81573025 to QL,81472637 to ZL,81672784 to ZL,and 81602200 to DL)+2 种基金Innovative Research Team in University of Liaoning(No.LT2017001 to QL)The program for climbing Scholars of Liaoning,Dalian High-level Talent Innovation Program(2016RD12 to QL)International Scientific and Technological Cooperation of Dalian(2015F11GH095 to QL).
文摘Background:Breast cancer stem cells(BCSCs)are considered responsible for cancer relapse and drug resistance.Understanding the identity of BCSCs may open new avenues in breast cancer therapy.Although several discoveries have been made on BCSC characterization,the factors critical to the origination of BCSCs are largely unclear.This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs.Methods:We detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency,and then performed target deep DNA sequencing at bulk-cell and single-cell levels.To identify the transcriptional program associated with BCSCs,bulk-cell and single-cell RNA sequencing was performed.Results:By using whole-genome sequencing of bulk cells,potential BCSC phenotype-associated mutation hotspot regions were detected.Validation by target deep DNA sequencing,at both bulk-cell and single-cell levels,revealed no genetic changes specifically associated with BCSC phenotype.Moreover,single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features.Notably,this transcriptomic variability was enriched during the transcription of 74 genes,revealed as BCSC markers.Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse,thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers.Conclusions:Transcriptomic variability,not genetic mutations,distinguishes BCSCs from non-BCSCs.The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.