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| Item Type: | Preprint |
|---|---|
| Title: | Lineage origin and developmental context shape tumor states in MYCN-dependent zebrafish neuroblastoma |
| Creators: |
Fresmann, Nora  ORCID: https://orcid.org/0000-0002-9233-5101, Köppke, Julia, Gauert, Anton ORCID: https://orcid.org/0000-0002-3013-5374, Senoussi, Anis ORCID: https://orcid.org/0000-0002-7066-8917, Olivares-Chauvet, Pedro ORCID: https://orcid.org/0009-0008-4684-255X, Grammatikaki, Aliki ORCID: https://orcid.org/0009-0000-8469-4254, Schott, Marie ORCID: https://orcid.org/0009-0000-7393-2421, Höfer, Lennart, Jens, Marvin ORCID: https://orcid.org/0000-0002-6660-8743, Beule, Dieter ORCID: https://orcid.org/0000-0002-3284-0632, Henssen, Anton G. ORCID: https://orcid.org/0000-0003-1534-778X, Rajewsky, Nikolaus ORCID: https://orcid.org/0000-0002-4785-4332, Spanjaard, Bastiaan ORCID: https://orcid.org/0000-0003-1309-8839, Hagemann, Anja I.H. ORCID: https://orcid.org/0000-0001-5491-4607 and Junker, Jan Philipp ORCID: https://orcid.org/0000-0002-2826-8290
|
| Abstract: | Neuroblastoma, a neural-crest-derived malignancy of the peripheral nervous system, is a devastating pediatric disease characterized by high intra- and intertumoral heterogeneity. While several tumor expression programs correlate with patient outcome, the developmental and contextual determinants of their emergence remain incompletely understood. Here, we systematically dissected neuroblastoma transcriptional heterogeneity and measured how tumor expression programs are associated with lineage history and developmental context. To achieve this, we combined single-cell transcriptomics with high-throughput lineage tracing and tumor cell transplantation in zebrafish models of MYCN-driven neuroblastoma. We identified developmental cell-state-associated programs that align with sympathoadrenal development, as well as general cellular-process programs. Clonal analysis showed that developmental programs are preferentially clone-associated, whereas cellular-process programs are more context-responsive. Transplantation into an embryonic environment reshaped the activation of several initially clone-associated programs, consistent with developmentally determined state reconfiguration and/or selection of state-competent cells. Together, our results show that lineage history and developmental context jointly shape tumor-state architecture in vivo. |
| Keywords: | Animals, Zebrafish |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2025.10.13.682025v2 |
| Date: | 3 August 2026 |
| Additional Information: | Accession "GSE301974", "GSE301860" and "GSE301869" are currently private and scheduled to be released on Nov 30, 2026. Custom code will be uploaded and made available through Github. |
| Official Publication: | https://doi.org/10.1101/2025.10.13.682025 |
| Related to: |
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