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

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

doi:10.1158/2159-8290.CD-24-1738

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	OF1-OF24
Journal	Cancer Discovery
Early online date	7 Aug 2025
DOIs	https://doi.org/10.1158/2159-8290.CD-24-1738
Publication status	E-pub ahead of print - 7 Aug 2025

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10.1158/2159-8290.CD-24-1738

Montuori et al_final_manuscriptAccepted author manuscript, 25.3 MBLicence: Creative Commons: Attribution (CC-BY)

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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., ... Dörr, J. R. (2025). Extrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers. Cancer Discovery, OF1-OF24. Advance online publication. https://doi.org/10.1158/2159-8290.CD-24-1738

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title = "Extrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers",

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.",

author = "Giulia Montuori and Fengyu Tu and Di Qin and Rachel Schmargon and Elias Rodriguez-Fos and Konstantin Helmsauer and Hui Hui and Susmita Mandal and Karin Purshouse and Lara Fankh{\"a}nel and Bartolomeo Bosco and Bastiaan Spanjaard and Hannah Seyboldt and Laura Grunewald and Schmitt, \{Matthias J{\"u}rgen\} and Dennis G{\"u}rgen and Viktoria Buck and Rosenfeldt, \{Mathias T.\} and Dubois, \{Frank P.B.\} and Simon Schallenberg and Annika Lehmann and Jessica Thei{\ss}en and Sabine Taschner-Mandl and Arend Koch and Patrick Hundsdoerfer and Annette K{\"u}nkele and Angelika Eggert and Matthias Fischer and Gaetano Gargiulo and Krieger, \{Teresa G.\} and Lukas Chavez and Fabian Coscia and Benjamin Werner and Weini Huang and Henssen, \{Anton G.\} and D{\"o}rr, \{Jan R.\}",

year = "2025",

month = aug,

day = "7",

doi = "10.1158/2159-8290.CD-24-1738",

language = "English",

pages = "OF1--OF24",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

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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, MJ, Gürgen, D, Buck, V, Rosenfeldt, MT, Dubois, FPB, Schallenberg, S, Lehmann, A, Theißen, J, Taschner-Mandl, S, Koch, A, Hundsdoerfer, P, Künkele, A, Eggert, A, Fischer, M, Gargiulo, G, Krieger, TG, Chavez, L, Coscia, F, Werner, B, Huang, W, Henssen, AG & Dörr, JR 2025, 'Extrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers', Cancer Discovery, pp. OF1-OF24. https://doi.org/10.1158/2159-8290.CD-24-1738

TY - JOUR

T1 - Extrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers

AU - Montuori, Giulia

AU - Tu, Fengyu

AU - Qin, Di

AU - Schmargon, Rachel

AU - Rodriguez-Fos, Elias

AU - Helmsauer, Konstantin

AU - Hui, Hui

AU - Mandal, Susmita

AU - Purshouse, Karin

AU - Fankhänel, Lara

AU - Bosco, Bartolomeo

AU - Spanjaard, Bastiaan

AU - Seyboldt, Hannah

AU - Grunewald, Laura

AU - Schmitt, Matthias Jürgen

AU - Gürgen, Dennis

AU - Buck, Viktoria

AU - Rosenfeldt, Mathias T.

AU - Dubois, Frank P.B.

AU - Schallenberg, Simon

AU - Lehmann, Annika

AU - Theißen, Jessica

AU - Taschner-Mandl, Sabine

AU - Koch, Arend

AU - Hundsdoerfer, Patrick

AU - Künkele, Annette

AU - Eggert, Angelika

AU - Fischer, Matthias

AU - Gargiulo, Gaetano

AU - Krieger, Teresa G.

AU - Chavez, Lukas

AU - Coscia, Fabian

AU - Werner, Benjamin

AU - Huang, Weini

AU - Henssen, Anton G.

AU - Dörr, Jan R.

PY - 2025/8/7

Y1 - 2025/8/7

N2 - 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.

AB - 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.

U2 - 10.1158/2159-8290.CD-24-1738

DO - 10.1158/2159-8290.CD-24-1738

M3 - Article

SN - 2159-8274

SP - OF1-OF24

JO - Cancer Discovery

JF - Cancer Discovery

ER -

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

Abstract

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