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000303426 1001_ $$00009-0007-9072-7156$$aMontuori, Giulia$$b0
000303426 245__ $$aExtrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers.
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000303426 520__ $$aExtrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting high-risk neuroblastoma, we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number-dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy-number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences cell fate decisions in cancer cell lines, patient-derived xenografts, and primary neuroblastomas, illustrating how extrachromosomal oncogene dosage-driven phenotypic diversity offers a strong evolutionary advantage under therapeutic pressure. Furthermore, we identify senescent cells with reduced ecDNA copy numbers as a source of treatment resistance in neuroblastomas and outline a strategy for their targeted elimination to improve the treatment of MYCN-amplified cancers.ecDNA-driven tumor genome evolution provides a major challenge to curative cancer therapies. We demonstrate that ecDNA copy-number dynamics drives treatment resistance by promoting oncogene dosage-dependent phenotypic heterogeneity in MYCN-amplified cancers. Exploiting phenotype-specific vulnerabilities of ecDNA cells, therefore, presents a powerful strategy to overcome treatment resistance. See related article by Korsah, p. XX.
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000303426 7001_ $$00000-0001-8748-7250$$aTu, Fengyu$$b1
000303426 7001_ $$00000-0002-9730-4072$$aQin, Di$$b2
000303426 7001_ $$00009-0009-3535-7185$$aSchmargon, Rachel$$b3
000303426 7001_ $$00000-0002-2555-0178$$aRodriguez-Fos, Elias$$b4
000303426 7001_ $$00000-0003-0773-4114$$aHelmsauer, Konstantin$$b5
000303426 7001_ $$00009-0001-0642-1522$$aHui, Hui$$b6
000303426 7001_ $$00000-0003-2248-7860$$aMandal, Susmita$$b7
000303426 7001_ $$00000-0003-0942-6342$$aPurshouse, Karin$$b8
000303426 7001_ $$00009-0008-3025-6871$$aFankhänel, Lara$$b9
000303426 7001_ $$00000-0002-3069-714X$$aBosco, Bartolomeo$$b10
000303426 7001_ $$00000-0003-1309-8839$$aSpanjaard, Bastiaan$$b11
000303426 7001_ $$00009-0005-3845-4459$$aSeyboldt, Hannah$$b12
000303426 7001_ $$00000-0002-7175-7380$$aGrunewald, Laura$$b13
000303426 7001_ $$aSchmitt, Matthias Jürgen$$b14
000303426 7001_ $$00000-0001-9241-6537$$aGürgen, Dennis$$b15
000303426 7001_ $$00000-0001-6123-1599$$aBuck, Viktoria$$b16
000303426 7001_ $$00000-0001-7650-8458$$aRosenfeldt, Mathias T$$b17
000303426 7001_ $$00000-0002-7654-6208$$aDubois, Frank P B$$b18
000303426 7001_ $$00000-0002-7897-7116$$aSchallenberg, Simon$$b19
000303426 7001_ $$00000-0001-9424-5882$$aLehmann, Annika$$b20
000303426 7001_ $$00000-0003-3182-1066$$aTheißen, Jessica$$b21
000303426 7001_ $$00000-0002-1439-5301$$aTaschner-Mandl, Sabine$$b22
000303426 7001_ $$00000-0001-8589-4688$$aKoch, Arend$$b23
000303426 7001_ $$00009-0007-1158-5170$$aHundsdoerfer, Patrick$$b24
000303426 7001_ $$00000-0002-8406-5412$$aKünkele, Annette$$b25
000303426 7001_ $$00000-0003-3476-8184$$aEggert, Angelika$$b26
000303426 7001_ $$00000-0003-1363-1242$$aFischer, Matthias$$b27
000303426 7001_ $$00000-0001-5414-4251$$aGargiulo, Gaetano$$b28
000303426 7001_ $$aKrieger, Teresa G$$b29
000303426 7001_ $$aChavez, Lukas$$b30
000303426 7001_ $$00000-0002-2244-5081$$aCoscia, Fabian$$b31
000303426 7001_ $$00000-0002-6857-8699$$aWerner, Benjamin$$b32
000303426 7001_ $$00000-0002-9016-2665$$aHuang, Weini$$b33
000303426 7001_ $$00000-0003-1534-778X$$aHenssen, Anton G$$b34
000303426 7001_ $$00000-0002-4927-6548$$aDörr, Jan R$$b35
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