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
Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany.
Group of Theoretical Biology, Innovation Center for Evolutionary Synthetic Biology, School of Life Science, Sun Yat-sen University, Guangzhou, China.
Cancer Discov. 2025 Aug 7:OF1-OF24. doi: 10.1158/2159-8290.CD-24-1738.
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.
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 article by Korsah, p. XX.
染色体外DNA（ecDNA）扩增通过不对称有丝分裂分离违反遗传继承的基本原理，增强细胞间癌基因剂量变异性并加速肿瘤进化。以高危神经母细胞瘤为重点，我们展示了ecDNA扩增如何破坏当前疗法在具有染色体外MYCN扩增的癌症中的临床疗效。将癌基因拷贝数依赖性适应性的理论模型与单细胞ecDNA定量和表型分析相结合，我们发现ecDNA拷贝数异质性驱动表型多样性，并通过染色体癌基因扩增无法实现的机制决定治疗敏感性。我们证明ecDNA拷贝数直接影响癌细胞系、患者来源的异种移植瘤和原发性神经母细胞瘤中的细胞命运决定，说明了染色体外癌基因剂量驱动的表型多样性如何在治疗压力下提供强大的进化优势。此外，我们将ecDNA拷贝数减少的衰老细胞鉴定为神经母细胞瘤治疗耐药的来源，并概述了一种针对其靶向消除的策略，以改善MYCN扩增癌症的治疗。
ecDNA驱动的肿瘤基因组进化对癌症根治性疗法构成重大挑战。我们证明ecDNA拷贝数动态通过促进MYCN扩增癌症中癌基因剂量依赖性表型异质性来驱动治疗耐药性。因此，利用ecDNA细胞的表型特异性弱点是克服治疗耐药性的有力策略。见Korsah的相关文章，第XX页。
