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

Bedoya-Reina O.C.,1, Li W.1, Arceo M.1, Plescher M.1, Bullova P1, Pui H.2, Kaucka M.3, Kharchenko P.4,5, Martinsson T.6, Holmberg J.7, Adameyko I.2,8, Deng Q.2 , Larsson C.9, Juhlin C.C.9 , Kogner P.10, Schlisio S.1

1, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. 2, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. 3, Max Planck Institute for Evolutionary Biology, Plön, Germany. 4, Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. 5, Harvard Stem Cell Institute, Cambridge, MA, USA. 6. Department of Pathology and Genetics, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. 7. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. 8, Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria. 9, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. 10, Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. In this study we interrogate single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compare tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland and provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a transcriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles a subtype of TRKB+ cholinergic progenitor population identified in human post-natal gland. Analyses of these populations reveal different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome.

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