Identification and Characterization of Adrenergic and Mesenchymal Cancer Cell States in Neuroblastoma Using Spatial-Omics [RNA-Seq]

ABSTRACT: Neuroblastoma is a pediatric cancer arising from the developing sympathoadrenal lineage and cell lines derived from neuroblastoma patients have features of either adrenergic neurons (ADRN) or mesenchymal cells (MES). However, identification of MES neuroblastoma cells in patient tumors has been challenging and controversial. This may be due to inter- or intra-patient tumor heterogeneity or discrepancies between the established neuroblastoma cell lines and patient tumors. To characterize the intra- and inter-patient cellular heterogeneity, we analyzed 54 neuroblastoma tumors, spanning a broad range of clinical, genetic, and histologic features. We combined single-cell/nucleus RNA-seq (sc/scRNA-seq), bulk RNA-seq, spatial transcriptomics, and spatial proteomics. We discovered that the tumor cells are in distinct cellular neighborhoods from the non-malignant immune and stromal cells, but we could not identify MES neuroblastoma cells using the established gene expression signatures developed from cell lines. However, using ADRN/MES gene expression signatures developed from early passage orthotopic patient-derived xenografts, we were able to identify MES neuroblastoma tumor cells. We validated our results using RNA-seq, RNA in situ hybridization, immunostaining, chromatin profiling, spatial transcriptomics, functional studies in organoids, and electron microscopy. MES neuroblastoma tumor cells were more likely to be found in high-risk, MYCN amplified post-treatment samples. Taken together, our results demonstrate that MES neuroblastoma tumor cells are present in patient tumors and may correlate with response to therapy and outcome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE348445 | GEO | 2026/09/23

REPOSITORIES: GEO