| Title: |
A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations |
| Authors: |
Saldana-Guerrero, I.M.; Montano-Gutierrez, L.F.; Boswell, K.; Hafemeister, C.; Poon, E.; Shaw, L.E.; Stavish, D.; Lea, R.A.; Wernig-Zorc, S.; Bozsaky, E.; Fetahu, I.S.; Zoescher, P.; Pötschger, U.; Bernkopf, M.; Wenninger-Weinzierl, A.; Sturtzel, C.; Souilhol, C.; Tarelli, S.; Shoeb, M.R.; Bozatzi, P.; Rados, M.; Guarini, M.; Buri, M.C.; Weninger, W.; Putz, E.M.; Huang, M.; Ladenstein, R.; Andrews, P.W.; Barbaric, I.; Cresswell, G.D.; Bryant, H.E.; Distel, M.; Chesler, L.; Taschner-Mandl, S.; Farlik, M.; Tsakiridis, A.; Halbritter, F. |
| Publisher Information: |
Nature Research |
| Publication Year: |
2024 |
| Collection: |
White Rose Research Online (Universities of Leeds, Sheffield & York) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
https://eprints.whiterose.ac.uk/id/eprint/212309/1/s41467-024-47945-7.pdf; Saldana-Guerrero, I.M. orcid.org/0000-0003-4064-185X , Montano-Gutierrez, L.F. orcid.org/0000-0003-2383-1483 , Boswell, K. orcid.org/0000-0002-1622-9673 et al. (34 more authors) (2024) A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations. Nature Communications, 15 (1). 3745. ISSN: 2041-1723 |
| Availability: |
https://eprints.whiterose.ac.uk/id/eprint/212309/ |
| Rights: |
cc_by_4 |
| Accession Number: |
edsbas.4E050784 |
| Database: |
BASE |