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| Item Type: | Dataset |
|---|---|
| Title: | Extrachromosomal DNA-driven oncogene dosage heterogeneity promotes rapid adaptation to therapy in MYCN-amplified cancers |
| Creators Name: | Coscia, Fabian |
| 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 critical 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 ecDNA-containing cells with reduced copy numbers in neuroblastomas and other MYC-amplified cancers as a source of treatment resistance and outline a strategy for their targeted elimination to improve the poor outcome of patients with MYCN-amplified cancers. |
| Keywords: | MYCN, Neuroblastoma, Proteomics |
| Source: | PRIDE |
| Publisher: | EMBL |
| Date: | 5 July 2025 |
| External Fulltext: | View full text on external repository or document server |
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