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Cited by 15Neuroblastoma Research and TreatmentsGenomic variations and chromosomal abnormalitiesCancer Genomics and Diagnostics

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Extrachromosomal DNA–Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN -Amplified Cancers

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Montuori, Giulia, Tu, Fengyu, Qin, Di, Schmargon, Rachel, Rodriguez-Fos, Elias, Helmsauer, Konstantin, Hui, Hui, Mandal, Susmita, Purshouse, Karin, Fankhänel, Lara, Bosco, Bartolomeo, Spanjaard, Bastiaan, Seyboldt, Hannah, Grunewald, Laura, Schmitt, Matthias Jürgen, Gürgen, Dennis, Buck, Viktoria, Rosenfeldt, Mathias T., Dubois, Frank P.B., Schallenberg, Simon, Lehmann, Annika, Theißen, Jessica, Taschner-Mandl, Sabine, Koch, Arend, Hundsdoerfer, Patrick, Künkele, Annette, Eggert, Angelika, Fischer, Matthias, Gargiulo, Gaetano, Krieger, Teresa G., Chavez, Lukas, Coscia, Fabian, Werner, Benjamin, Huang, Weini, Henssen, Anton G., Dörr, Jan R.·2025·Cancer Discovery
DOI 10.1158/2159-8290.cd-24-1738PMC PMC12456741

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Abstract

Extrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting high-risk neuroblastoma, we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number–dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy-number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences cell fate decisions in cancer cell lines, patient-derived xenografts, and primary neuroblastomas, illustrating how extrachromosomal oncogene dosage–driven phenotypic diversity offers a strong evolutionary advantage under therapeutic pressure. Furthermore, we identify senescent cells with reduced ecDNA copy numbers as a source of treatment resistance in neuroblastomas and outline a strategy for their targeted elimination to improve the treatment of MYCN-amplified cancers. Significance: ecDNA-driven tumor genome evolution provides a major challenge to curative cancer therapies. We demonstrate that ecDNA copy-number dynamics drives treatment resistance by promoting oncogene dosage–dependent phenotypic heterogeneity in MYCN-amplified cancers. Exploiting phenotype-specific vulnerabilities of ecDNA cells, therefore, presents a powerful strategy to overcome treatment resistance. See related commentary by Korsah, p. 1979

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Metadata

Authors
Montuori, G., Tu, F., Qin, D., Schmargon, R., Rodriguez-Fos, E., Helmsauer, K., Hui, H., Mandal, S., Purshouse, K., Fankhänel, L., Bosco, B., Spanjaard, B., Seyboldt, H., Grunewald, L., Schmitt, M. J., Gürgen, D., Buck, V., Rosenfeldt, M. T., Dubois, F. P. B., Schallenberg, S., Lehmann, A., Theißen, J., Taschner-Mandl, S., Koch, A., Hundsdoerfer, P., Künkele, A., Eggert, A., Fischer, M., Gargiulo, G., Krieger, T. G., Chavez, L., Coscia, F., Werner, B., Huang, W., Henssen, A. G., & Dörr, J. R.
Affiliations
  • Humboldt-Universität zu Berlin (DE)
  • Sun Yat-sen University (CN)
  • Max Delbrück Center (DE)
  • 1Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany.
  • Sanford Burnham Prebys Medical Discovery Institute (US)
  • Institute of Genetics and Cancer (GB)
  • 10Experimental Pharmacology and Oncology (EPO), Berlin, Germany.
  • University of Würzburg (DE)
  • University of Cologne (DE)
  • 13St. Anna Children’s Cancer Research Institute, Vienna, Austria.
  • 15Department of Pediatric Oncology, Helios Klinikum Berlin-Buch, Berlin, Germany.
  • German Cancer Research Center (DE)
  • 7Sanford Burnham Prebys Medical Discovery Institute, San Diego, California.
  • Queen Mary University of London (GB)
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2025-08-07
Volume
15
Issue
10
Pages
2054-2077
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-24-1738
PMC
PMC12456741
OpenAlex
W4413045433
Cited by
15
References
103
Citations by year
2026: 14 · 2025: 1
FWCI
9.13
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (CRC1588)
  • Deutsche Krebshilfe (70114107)
  • HORIZON EUROPE European Research Council (949172)
  • Berlin Center for Machine Learning (161L0222)
  • National Cancer Institute (CA030199)
  • UK Research and Innovation (MR/V02342X/1)
  • Cancer Research UK (398299703)
  • National Institute of Neurological Disorders and Stroke (NS132780)
  • Berlin Institute of Health (Clinician Scientist Program)
Topics
  • Health Sciences › Medicine › Oncology › Neuroblastoma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
extrachromosomal DNA, MYCN amplification, neuroblastoma, treatment resistance, tumor evolution, phenotypic heterogeneity, senescent cells
MeSH terms
N-Myc Proto-Oncogene Protein, Animals, Gene Amplification, Humans, Neuroblastoma, Gene Dosage, Genetic Heterogeneity, Drug Resistance, Neoplasm, Cell Line, Tumor, Mice, DNA Copy Number Variations

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