Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Abstract

Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

Single-nuclei transcriptomes from human adrenal gland reveal distinct cellular identities of low and high-risk neuroblastoma tumors

“…Oppositely, the undifferentiated cluster nC3 shared a significant number of upregulated genes with neural-crest cell-like signature 15 and MES (i.e., mesenchymal) 16 signatures. g A comparison of the gene-specific signature of NB clusters with markers defining clusters in eight tumors previously sequenced with 10X 13 , suggests a more significant similarity of the noradrenergic clusters (nC5, nC7, nC8, and nC9) with tumor clusters 1, 2, and 3; and of the undifferentiated nC3 cluster with the tumor cluster 3 13 . Only clusters with the most significant similarities are displayed.…”

“…2c, d , Supplementary Data 5 ). No progenitor cells other than SCP, chromaffin, and sympathoblast populations have been described for fetal adrenal gland 13 , 14 . In this regard, the only gene signatures shared with human fetal adrenal gland and mouse embryonic anlagen belonged to cell-cycle genes expressed in cycling sympathoblast (mouse E13 and human 8–14 PCW) and cycling chromaffin (human 8–14 PCW, FDR < 0.05, Fisher’s exact test, Supplementary Data 5 ).…”

“…Here we deep-sequence full-length coverage RNA from single nuclei of tumors ( n = 11) across different risk groups and cross-compare cell clusters transcriptomes with healthy postnatal adrenal gland (human n = 3, mouse n = 5). We further include recently published single-cell sequencing datasets from 10X single-sequenced NB tumors ( n = 8) 13 , E12–E13 embryonic mouse adrenal anlagen 6 , human fetal adrenal gland 14 , and the transcriptional profiles of neuroblastoma mesenchymal-/NCC-like and (nor-)adrenergic cell lineages 15 , 16 . We identify a cluster of TRKB+ cholinergic cells unique to human postnatal adrenal gland, that differ from previously described embryonic Schwann cell precursors (SCP).…”

Future Match Making: When Pediatric Oncology Meets Organoid Technology

“…Thus, alterations in epigenetic processes involved in cell specification and plasticity appear to be central in pediatric oncology. With the recent democratization of single-cell RNA-sequencing, increasing evidences support that pediatric cancers are hierarchically organized tumors recapitulating impaired developmental trajectories and possessing CSC responsible for maintenance, relapse, and metastasis of the tumor ( Couturier et al, 2020 ; Gojo et al, 2020 ; Kildisiute et al, 2021 ). Then, our ability to reconstruct intratumoral hierarchy and dynamics in pediatric cancer models is therefore crucial for understanding pediatric cancer biology.…”

Bone Marrow Environment in Metastatic Neuroblastoma

“…Presently, conflicting results have been published [ 57 , 58 , 59 , 60 , 61 ] regarding their developmental origin, but definitive results will certainly come in the next few years. As for the plasticity, it is interesting to note that already in 2007, Martinez et al described the presence of GD2+/CD45− cells with mesenchymal phenotype in the BM of children with NB [ 62 ].…”