Integrated analysis of single-cell and bulk transcriptomes uncovers clinically relevant molecular subtypes in human prostate cancer  

作　　者：Tao Ding Lina He Guowen Lin Lei Xu Yanjun Zhu Xinan Wang Xuefei Liu Jianming Guo Fanghong Lei Zhixiang Zuo Jianghua Zheng 

机构地区：[1]Department of Urology,Yuebei People’s Hospital,Shantou University Medical College,Shaoguan 512025,China [2]Department of Urology,Southern Medical University Affifiliated Fengxian Hospital,Shanghai 201499,China [3]School of Life Sciences,State Key Laboratory of Oncology in South China,Cancer Center,Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University,Guangzhou 510060,China [4]Department of Urology,Fudan University Shanghai Cancer Center,Shanghai 200032,China [5]Department of Urology,Zhongshan Hospital,Fudan University,Shanghai 200032,China [6]Department of Urology,Tongji Hospital,School of Medicine,Tongji University,Shanghai 200065,China [7]Department of Biochemistry,School of Medicine,Southern University of Science and Technology,Shenzhen 518055,China [8]Department of Pathology,Yuebei People’s Hospital,Shantou University Medical College,Shaoguan 512025,China [9]Central Laboratory,Tongji Hospital,School of Medicine,Tongji University,Shanghai 200065,China [10]Department of Laboratory Medicine,Shanghai University of Medicine&Health Sciences Affiliated Zhoupu Hospital,Shanghai 201318,China

出　　处：《Chinese Journal of Cancer Research》2025年第1期90-114,共25页中国癌症研究(英文版)

基　　金：supported by Shanghai Science and Technology Commission,China(No.21S11902100);Shanghai Municipal Health Commission Scientific Research Project(No.202140308);Clinical Research Project of Tongji Hospital of Tongji University[No.ITJ(ZD)2209];Shanghai Tongji Hospital National Natural Science Foundation Cultivation Project(No.GJPY2216);Shanghai Medical Innovation Research Special Foundation(No.23Y11908800);CSCO-Haosen Oncology Research Fund(No.Y-HS202301-0096).

摘　　要：Objective:Prostate cancer(PCa)is a complex disease characterized by diverse cellular ecosystems within the tumor microenvironment(TME)and high tumor heterogeneity,which challenges clinically stratified management and reinforces the need for novel strategies to fight against castration-resistant PCa(CRPC).Methods:We performed single-cell RNA sequencing(scRNA-seq)on 10 untreated primary PCa tissues and integrated public scRNA-seq resources from three normal prostate tissues,two untreated primary PCa tissues,and six CRPC tumors to portray a comprehensive cellular and molecular interaction atlas of PCa.We further integrated the single-cell and bulk transcriptomes of PCa to establish a molecular classification system.Results:scRNA-seq profiles revealed substantial inter-and intra-tumoral heterogeneity across different cell subpopulations in untreated PCa and CRPC tumors.In the malignant epithelial reservoir,cells evolved along decoupled paths in treatment-naive PCa and CRPC tumors,and distinct transcriptional reprogramming processes were activated,highlighting anti-androgen therapy-induced lineage plasticity.Based on the specifically expressed markers of the epithelial subpopulations,we conducted unsupervised clustering analysis in The Cancer Genome Atlas prostate adenocarcinoma(TCGA-PRAD)cohort and identified three molecularly and clinically distinct subtypes.The C1 subtype,characterized by high enrichment of CRPC-enriched epithelial cells,had a high risk of rapid development of anti-androgen resistance and might require active surveillance and additional promising intervention treatments,such as integrin A3(ITGA3)+integrin B1(ITGB1)inhibition.The C2 subtype resembled the immune-modulated subtype that was most likely to benefit from anti-LAG3 immunotherapy.The C3 subtype had a favorable prognosis.Conclusions:Our study provides a comprehensive and high-resolution landscape of the intricate architecture of the PCa TME,and our trichotomic molecular taxonomy could help facilitate precision oncology.

关 键 词：Single-cell RNA sequencing prostate cancer lineage plasticity tumor heterogeneity molecular classification 

分 类 号：R737.25[医药卫生—肿瘤]