Single-cell MultiOmics and spatial transcriptomics demonstrate neuroblastoma developmental plasticity
Yunyun Xu, Daohua Lou, Ping Chen, Gang Li, Dimtry Usoskin, Jian Pan, Fang Li, Shungen Huang, Caroline Hess, Ruze Tang, Xiaohan Hu, Juanjuan Yu, Maria Arceo, Ronald R. de Krijger, Arthur S. Tischler, Susanne Schlisio, Patrik Ernfors, Yizhou Hu, Jian Wang
Abstract
Neuroblastoma, the most prevalent extracranial pediatric solid tumor, arises from neural crest progeny cells. It exhibits substantial developmental plasticity and intratumoral heterogeneity, leading to survival rates below 50% in high-risk cases. The regulatory mechanisms underlying this plasticity remain largely elusive. In this integrative study, we used single-cell MultiOmics from a mouse spontaneous tumor model and spatial transcriptomics from human patient samples to dissect the transcriptional and epigenetic landscapes that govern developmental states in neuroblastoma. We identified developmental intermediate states in high-risk neuroblastomas critical for malignant transitions and uncovered extensive epigenetic priming with latent capacity for diverse state transitions. Furthermore, we mapped enhancer gene regulatory networks (eGRNs) and tumor microenvironments sustaining these aggressive states. State transitions and malignancy could be interfered with by targeting transcription factors controlling the eGRNs.