Intercellular extrachromosomal DNA copy-number heterogeneity drives neuroblastoma cell state diversity
Neuroblastoma exhibits significant inter- and intra-tumor genetic heterogeneity and varying clinical outcomes. Extrachromosomal DNAs (ecDNAs) may drive this heterogeneity by independently segregating during cell division, leading to rapid oncogene amplification. While ecDNA-mediated oncogene amplification is linked to poor prognosis in various cancers, the effects of ecDNA copy-number heterogeneity on intermediate phenotypes are poorly understood. Here, we leverage DNA and RNA sequencing from the same single cells in cell lines and neuroblastoma patients to investigate these effects. By analyzing ecDNA amplicon structures, we reveal extensive intercellular ecDNA copy-number heterogeneity. We also provide direct evidence of how this heterogeneity influences the expression of cargo genes, including MYCN and its downstream targets, and the overall transcriptional state of neuroblastoma cells. Our findings highlight the role of ecDNA copy number in promoting rapid adaptability of cellular states within tumors, underscoring the need for ecDNA-specific treatment strategies to address tumor formation and adaptation.
Authors
- Anton George Henssen (ORCID: https://orcid.org/0000-0003-1534-778X)
- Nadine Wittstruck (ORCID: https://orcid.org/0009-0000-4378-3226)
- Annabell Szymansky (ORCID: https://orcid.org/0000-0003-4797-4526)
- Rocío Chamorro González (ORCID: https://orcid.org/0000-0002-5653-7259)
- Maja C Stöber (ORCID: https://orcid.org/0000-0002-6679-5577)
- Lotte Brückner (ORCID: https://orcid.org/0000-0002-6155-2277)
- Johannes H. Schulte (ORCID: https://orcid.org/0000-0003-0671-1201)
- Angelika Eggert (ORCID: https://orcid.org/0000-0003-3476-8184)
- Thomas Conrad (ORCID: https://orcid.org/0000-0001-5618-6295)
- Roland F. Schwarz (ORCID: https://orcid.org/0000-0001-9155-4268)
- Richard P. Koche (ORCID: https://orcid.org/0000-0002-6820-5083)
- Kerstin Haase (ORCID: https://orcid.org/0000-0002-0944-5618)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- German Cancer Research Center (DE)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- Humboldt-Universität zu Berlin (DE)
- German Cancer Society (DE)
- University Hospital Cologne (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114711
- Citations
- 21
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 7.38
Funders
- CERN
- Cancer Research UK
- European Commission
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- Berlin Institute of Health
- Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona
- National Institutes of Health
- Berlin Center for Machine Learning