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

Abstract

<jats:title>Abstract</jats:title><jats:p>Neuroblastoma is an embryonal childhood cancer that arises from aberrant development of the neural crest, mostly within the fetal adrenal medulla. 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=16,591) with 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 652 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that there exists a pan-neuroblastoma cancer cell state which may be an attractive target for novel therapeutic avenues.</jats:p><jats:sec><jats:title>One Sentence Summary</jats:title><jats:p>Comparisons of neuroblastoma cells and relevant normal cells reveal a uniform cell state that characterizes neuroblastoma across patients and disease phenotypes.</jats:p></jats:sec>

Single cell derived mRNA signals across human kidney tumors

“…1C ), strongly resemble mesenchymal cells in the fetal adrenal ( Fig. S1D ) 12 , and both populations resemble primitive mesodermal populations in the post gastrulation mouse embryo ( Fig. S1D ) 13 .…”

“…We combined this refined map of the developing kidney with previously generated maps of the mature kidney 1 , the developing adrenal gland 12 , and the post-gastrulation mouse 13 ( Fig. 1A ).…”

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

“…In support of this finding, previously described SCPs from mouse adrenal anlagen at embryonic day E12/E13 [6], and from human fetal adrenal glands at 8-14 post-conception weeks (PCW) [14] shared no significant specific gene signature with the human post-natal progenitor cluster hC1 (Fisher's exact test, Supplementary Figure 2 c-d, Supplementary Table 3). No other progenitor cells than SCP, chromaffin and sympathoblast populations have been described for fetal adrenal gland [13,14]. In this regard, the only shared gene signatures with human fetal adrenal gland and mouse embryonic anlagen belonged to cell-cycle genes expressed in the cycling sympathoblast (mouse E13 and human 8-14 PCW) and cycling chromaffin (human 8-14 PCW, FDR<0.05, Fisher's exact test, Supplementary Table 3).…”

“…Consistently with this observation, the undifferentiated nC3 cluster shared a significant number of up-regulated genes with the neural crest cells-like signature (group II) and the mesenchymal (MES) gene expression signatures previously described in neuroblastoma cell lines [15,16], while the noradrenergic clusters nC5, nC7, nC8, and nC9 presented a significantly high expression of genes characterizing the sympathetic noradrenergic (group I) and ADR (adrenergic) signatures (FDR<0.01, Fisher's exact test, Figure 3e-f, Supplementary Table 4). Additionally, specific gene signatures from each neuroblastoma cluster was compared with the recently described markers of six cell-clusters in eight GOSH-cohort tumors sequenced with 10X [13]. The noradrenergic clusters nC5, nC7, nC8, and nC9 resembled more significantly the GOSH sympathoblast-like tumors clusters 1, 2, and 3, whereas the undifferentiated cluster nC3 showed a higher significant resemblance with the less differentiated GOSH-tumor cluster 3 (FDR<0.01, Fisher's exact test, Figure 3g, Supplementary Table 4).…”

“…Further, cell clusters were identified, and their transcriptomes were cross-compared with those of cell clusters obtained from healthy tissue where the malignancy is commonly detected, specifically with human (n=3) and mouse (n=5) post-natal adrenal glands. For this comparison we also included 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 identified a cluster of TRKB+ cholinergic cells in the human post-natal adrenal gland, that differ from previously described embryonic Schwann cell precursors (SCP).…”