Single-cell profiling of peripheral neuroblastic tumors identifies an aggressive transitional state that bridges an adrenergic-mesenchymal trajectory
Xiaojun Yuan,
Janith A. Seneviratne,
Shibei Du,
Ying Xu,
Yijun Chen,
Qianya Jin,
Xuanxuan Jin,
Anushree Balachandran,
Shihao Huang,
Yanli Xu,
Yue Zhai,
Liumei Lu,
Mengjie Tang,
Yushuang Dong,
Belamy B. Cheung,
Glenn M. Marshall,
Weiyang Shi,
Daniel R. Carter,
Chao Zhang
Affiliations
Xiaojun Yuan
Department of Pediatric Hematology & Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Janith A. Seneviratne
Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
Shibei Du
Department of Pediatric Hematology & Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Ying Xu
Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 201619, China
Yijun Chen
Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 201619, China
Qianya Jin
Department of Pediatric Hematology & Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Xuanxuan Jin
Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 201619, China
Anushree Balachandran
Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia
Shihao Huang
Department of Pediatric Hematology & Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Yanli Xu
Department of Pediatric Hematology & Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Yue Zhai
Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 201619, China
Liumei Lu
Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 201619, China
Mengjie Tang
Department of Pediatric Hematology & Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Yushuang Dong
Department of Pediatric Hematology & Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Belamy B. Cheung
Department of Pediatric Hematology & Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China; Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; School of Women’s and Children’s Health, UNSW Sydney, Randwick, NSW 2031, Australia
Glenn M. Marshall
Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; School of Women’s and Children’s Health, UNSW Sydney, Randwick, NSW 2031, Australia; Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW 2031, Australia
Weiyang Shi
Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao, China; Corresponding author
Daniel R. Carter
Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 201619, China; School of Women’s and Children’s Health, UNSW Sydney, Randwick, NSW 2031, Australia; School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia; Corresponding author
Chao Zhang
Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 201619, China; Corresponding author
Summary: Peripheral neuroblastic tumors (PNTs) represent a spectrum of neural-crest-derived tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Malignant cells in PNTs are theorized to interconvert between adrenergic/noradrenergic and mesenchymal/neural crest cell states. Here, single-cell RNA-sequencing analysis of 10 PNTs demonstrates extensive transcriptomic heterogeneity. Trajectory modeling suggests that malignant neuroblasts move between adrenergic and mesenchymal cell states via an intermediate state that we term “transitional.” Transitional cells express programs linked to a sympathoadrenal development and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature is predictive of poor prognosis compared with adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identifies a similar transitional H3K27-acetylation super-enhancer landscape. Collectively, our study supports the concept that PNTs have phenotypic plasticity and uncovers potential biomarkers and therapeutic targets.
