Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma
Neuroblastoma (NB) is one of the most lethal childhood cancers due to its propensity to become treatment resistant. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicate these two contrasting scenarios and show branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.
Authors
- Adriana Mañas (ORCID: https://orcid.org/0000-0002-6955-1754)
- Daniel Bexell (ORCID: https://orcid.org/0000-0001-9426-9550)
- David Gisselsson (ORCID: https://orcid.org/0000-0002-0301-426X)
- Anders Valind (ORCID: https://orcid.org/0000-0002-1654-6978)
- Karin Hansson (ORCID: https://orcid.org/0000-0002-6993-7673)
- Minjun Yang (ORCID: https://orcid.org/0000-0002-3324-1498)
- Kristina Aaltonen (ORCID: https://orcid.org/0000-0001-5104-735X)
- Natalie Andersson (ORCID: https://orcid.org/0000-0002-3643-4404)
- Naveen Ravi (ORCID: https://orcid.org/0000-0002-3849-8487)
- Subhayan Chattopadhyay (ORCID: https://orcid.org/0000-0002-8599-2971)
- Diana C.J. Spierings (ORCID: https://orcid.org/0000-0001-8403-474X)
- Geoffroy Durand (ORCID: https://orcid.org/0000-0001-9004-7248)
- Caroline Jansson (ORCID: https://orcid.org/0009-0001-4115-0414)
- Floris Foijer (ORCID: https://orcid.org/0000-0003-0989-3127)
- Kajsa Paulsson (ORCID: https://orcid.org/0000-0001-7950-222X)
- Jenny Karlsson (ORCID: https://orcid.org/0000-0001-7681-0059)
- Hiroaki Yasui (ORCID: https://orcid.org/0000-0002-2607-5233)
- Michele Ferro
Institutions
- University Medical Center Groningen (NL)
- University of Groningen (NL)
- Lund University (SE)
- Scandinavian Sarcoma Group (Sweden) (SE)
- Skåne University Hospital (SE)
- Nagoya University (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1038/s41467-024-53334-x
- Citations
- 9
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 3.32
Funders
- Cancerfonden
- Lunds Universitet
- Vetenskapsrådet
- Barncancerfonden
- Science for Life Laboratory