Neuroblastoma-associated chromosomal aberrations drive cell identity loss in human neural crest via disruption of developmental regulators

Saldana-Guerrero, I. M.; Montano-Gutierrez, L. F.; Hafemeister, C.; Stavish, D.; Shaw, L. E.; Fetahu, I. S.; Wenninger-Weinzierl, A.; Sturtzel, C.; Souilhol, C.; Tarelli, S.; Shoeb, M. R.; Bernkopf, M.; Bozatzi, P.; Guarini, M.; Bozsaky, E.; Buri, M. C.; Putz, E. M.; Andrews, P. W.; Barbaric, I.; Bryant, H. E.; Distel, M.; Taschner-Mandl, S.; Farlik, M.; Tsakiridis, A.; Halbritter, F.

doi:10.1101/2022.11.21.515753

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bioRxiv · 10.1101/2022.11.21.515753

Neuroblastoma-associated chromosomal aberrations drive cell identity loss in human neural crest via disruption of developmental regulators

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Abstract

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.

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Saldana-Guerrero, I. M., Montano-Gutierrez, L. F., Hafemeister, C., Stavish, D., Shaw, L. E., Fetahu, I. S., Wenninger-Weinzierl, A., Sturtzel, C., Souilhol, C., Tarelli, S., Shoeb, M. R., Bernkopf, M., Bozatzi, P., Guarini, M., Bozsaky, E., Buri, M. C., Putz, E. M., Andrews, P. W., Barbaric, I., Bryant, H. E., Distel, M., Taschner-Mandl, S., Farlik, M., Tsakiridis, A., Halbritter, F.. 2022-11-23. Neuroblastoma-associated chromosomal aberrations drive cell identity loss in human neural crest via disruption of developmental regulators. https://doi.org/10.1101/2022.11.21.515753

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