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

doi:10.1016/j.celrep.2022.111455

Single-cell profiling of peripheral neuroblastic tumors identifies an aggressive transitional state that bridges an adrenergic-mesenchymal trajectory

Cell Rep. 2022 Oct 4;41(1):111455. doi: 10.1016/j.celrep.2022.111455.

Authors

Xiaojun Yuan¹, Janith A Seneviratne², Shibei Du¹, Ying Xu³, Yijun Chen³, Qianya Jin¹, Xuanxuan Jin³, Anushree Balachandran², Shihao Huang¹, Yanli Xu¹, Yue Zhai³, Liumei Lu³, Mengjie Tang¹, Yushuang Dong¹, Belamy B Cheung⁴, Glenn M Marshall⁵, Weiyang Shi⁶, Daniel R Carter⁷, Chao Zhang⁸

Affiliations

¹ Department of Pediatric Hematology & Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
² Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia.
³ Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 201619, China.
⁴ 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.
⁵ 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.
⁶ Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao, China. Electronic address: wshi@ouc.edu.cn.
⁷ 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. Electronic address: daniel.carter@uts.edu.au.
⁸ Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 201619, China. Electronic address: zhangchao@tongji.edu.cn.

PMID: 36198269
DOI: 10.1016/j.celrep.2022.111455

Abstract

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.

Keywords: CP: Cancer; adrenergic; ganglioneuroblastoma; heterogeneity; mesenchymal; microenvironment; neuroblastoma; plasticity; scRNA-seq; tumor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adrenergic Agents
Ganglioneuroblastoma* / genetics
Ganglioneuroblastoma* / metabolism
Ganglioneuroblastoma* / pathology
Ganglioneuroma* / genetics
Ganglioneuroma* / metabolism
Ganglioneuroma* / pathology
Humans
Neuroblastoma* / pathology
RNA

Substances

Adrenergic Agents
RNA