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Joint single-cell genetic and transcriptomic analysis reveal embedded premalignant subclones and progressive cell states in human neuroblastoma

ABSTRACT: Neuroblastoma is a heterogeneous embryonal malignancy and the deadliest tumor of infancy. While its exact origin is still under debate, it is assumed to arise from the multipotent neural crest. To understand the origin and clonal development of various neuroblastoma cell states, we analyzed human tumor samples using single-cell multi-omics, including joint DNA/RNA sequencing of sorted single cells (DNTR-seq). Tumor subclones showed considerable inter- individual variation in terms of copy number profiles and transcriptional phenotype. Despite this heterogeneity, transcriptional plasticity between subclones converges on cellular processes related to axon guidance via the SLIT/ROBO pathway, proliferation, and differentiation. Genomic heterogeneity was also observed for MYCN. Subclones harboring 2p/MYCN gain (< 8 copies) co-exist with amplified subclones (> 20 copies), indicating that MYCN amplification may represent a non-initiating genomic event. Beyond adrenergic heterogeneity, we identify a subpopulation of abnormal cells resembling multipotent Schwann cell precursors, characterized by expression programs of proliferation, apoptosis, and a non- immunomodulatory phenotype. Their genomic profile and phylogeny suggest an ancestral, pre-malignant role in tumorigenesis. While the function of these SCP-like cells in tumor initiation remains to be established, their identification expands the reservoir of tumor cells, considering their multipotency reflecting a central neuroblastoma feature.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261828 | GEO | 2024/09/13

REPOSITORIES: GEO

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Project description:In neuroblastoma, amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN is the defining prognosticator of high-risk disease, occurs in one-third of neuroblastoma, and drastically reduces overall survival rates. As a proto-oncogene, targeted MYCN overexpression in peripheral neural crest is sufficient to initiate disease in mouse models. In MYCN amplified neuroblastoma, elevated expression of the factor is crucial to maintain tumor stemness and is associated with increased proliferation and aberrant cell cycle progression, as these tumors lack the ability to arrest in G1 in response to irradiation. MYCN down-regulation broadly reverses these oncogenic phenotypes in a variety of neuroblastoma models and recent thereapeutic strategies to indirectly target MYCN production or protein stability have reduced tumor growth in vivo. These observations motivate an investigation of MYCN binding in MYCN amplified tumors as it remains fundamentally unclear how elevated levels of the factor occupy the genome and alter transcriptional programs in neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of direct MYCN perturbation in neuroblastoma. We find that at oncogenic levels, MYCN associates with E-box (CANNTG) binding motifs in an affinity dependent manner across most active cis-regulatory promoters and enhancers. MYCN shutdown globally reduces histone acetylation and transcription, consistent with prior descriptions of MYC proteins as non-linear amplifiers of gene expression. We establish that MYCN load at the promoter and proximal enhancers predicts transcriptional responsiveness to MYCN shutdown and that MYCN enhancer binding occurs prominently at the most strongly occupied and down-regulated genes, suggesting a role for these tissue specific elements in predicating MYCN responsive âtargetâ genes. At these invaded enhancers, we identify the lineage specific bHLH TWIST1 as a key collaborator and dependency of oncogenic MYCN. These data suggest that MYCN enhancer invasion helps shape transcriptional amplification of the neuroblastoma gene expression program to promote tumorigenesis. ChIP-Seq in SHEP21, BE2C, KELLY, and NGP neuroblastoma cell lines for H3K27ac, H3K4me3, RNA PolII, MYCN, BRD4, or TWIST1

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Joint single-cell genetic and transcriptomic analysis reveal embedded premalignant subclones and progressive cell states in human neuroblastoma

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