A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations

• Published in: Nature communications Vol. 15; no. 1; p. 3745
• Main Authors: Saldana-Guerrero, Ingrid M., Montano-Gutierrez, Luis F., Boswell, Katy, Hafemeister, Christoph, Poon, Evon, Shaw, Lisa E., Stavish, Dylan, Lea, Rebecca A., Wernig-Zorc, Sara, Bozsaky, Eva, Fetahu, Irfete S., Zoescher, Peter, Pötschger, Ulrike, Bernkopf, Marie, Wenninger-Weinzierl, Andrea, Sturtzel, Caterina, Souilhol, Celine, Tarelli, Sophia, Shoeb, Mohamed R., Bozatzi, Polyxeni, Rados, Magdalena, Guarini, Maria, Buri, Michelle C., Weninger, Wolfgang, Putz, Eva M., Huang, Miller, Ladenstein, Ruth, Andrews, Peter W., Barbaric, Ivana, Cresswell, George D., Bryant, Helen E., Distel, Martin, Chesler, Louis, Taschner-Mandl, Sabine, Farlik, Matthias, Tsakiridis, Anestis, Halbritter, Florian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 42/44; 45/100; 45/22; 45/23; 45/77; 45/88; 45/90; 59/57; 631/136/1425; 631/136/532; 631/208/69; 631/67/1678; 631/67/2332; 64/116; 64/60; 82/1; 82/51; 96/106; 96/2; 96/21; 96/31; 96/34; 96/35; 96/63; Aberration; Adrenal glands; Cell Differentiation; Cell Line, Tumor; Children; Chromosome 17; Chromosome Aberrations; Chromosomes; Copy number; Differentiation; DNA Copy Number Variations; Embryo cells; Female; Gene Expression Regulation, Neoplastic; Human Embryonic Stem Cells - metabolism; Humanities and Social Sciences; Humans; multidisciplinary; N-Myc Proto-Oncogene Protein - genetics; N-Myc Proto-Oncogene Protein - metabolism; Neural crest; Neural Crest - metabolism; Neural Crest - pathology; Neural stem cells; Neuroblastoma; Neuroblastoma - genetics; Neuroblastoma - pathology; Science; Science (multidisciplinary); Stem cells; Sympathetic nervous system; Transcriptome; Transcriptomes; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47945-7

Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ female human embryonic stem cell (hESC) differentiation and single-cell transcriptome and epigenome analysis to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB). We show that CNAs impair the specification of trunk neural crest (NC) cells and their sympathoadrenal derivatives, the putative cells-of-origin of NB. This effect is exacerbated upon overexpression of MYCN , whose amplification co-occurs with CNAs in NB. Moreover, CNAs potentiate the pro-tumourigenic effects of MYCN and mutant NC cells resemble NB cells in tumours. These changes correlate with a stepwise aberration of developmental transcription factor networks. Together, our results sketch a mechanistic framework for the CNA-driven initiation of embryonal tumours. Copy number alterations in stem cells impair neural crest differentiation and set the stage for neuroblastoma-like traits and tumours. This study hints at early tumourigenesis mechanisms and finds developmental gene signatures linked to prognosis.