MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC

Elena Fiorini, Antonia Malinova, Daniel Schreyer, Davide Pasini, Michele Bevere, Giorgia Alessio, Diego Rosa, Sabrina D’Agosto, Luca Azzolin, Salvatore Milite, Silvia Andreani, Francesca Lupo, Lisa Veghini, Sonia Grimaldi, Serena Pedron, Monica Castellucci, Craig Nourse, Roberto Salvia, Giuseppe Malleo, Andrea Ruzzenente, Alfredo Guglielmi, Michele Milella, Rita T. Lawlor, Claudio Luchini, Antonio Agostini, Carmine Carbone, Christian Pilarsky, Andrea Sottoriva, Aldo Scarpa, David A. Tuveson, Peter Bailey () and Vincenzo Corbo ()
Additional contact information
Elena Fiorini: University of Verona
Antonia Malinova: University of Verona
Daniel Schreyer: University of Glasgow
Davide Pasini: University of Verona
Michele Bevere: University of Verona
Giorgia Alessio: University of Verona
Diego Rosa: University of Verona
Sabrina D’Agosto: University of Verona
Luca Azzolin: Human Technopole
Salvatore Milite: Human Technopole
Silvia Andreani: University of Verona
Francesca Lupo: University of Verona
Lisa Veghini: University of Verona
Sonia Grimaldi: University of Verona
Serena Pedron: University of Verona
Monica Castellucci: University of Verona
Craig Nourse: Cancer Research UK Beatson Institute
Roberto Salvia: University of Verona
Giuseppe Malleo: University of Verona
Andrea Ruzzenente: University of Verona
Alfredo Guglielmi: University of Verona
Michele Milella: University of Verona
Rita T. Lawlor: University of Verona
Claudio Luchini: University of Verona
Antonio Agostini: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Carmine Carbone: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Christian Pilarsky: Universitätsklinikum Erlangen
Andrea Sottoriva: Human Technopole
Aldo Scarpa: University of Verona
David A. Tuveson: Cold Spring Harbor Laboratory
Peter Bailey: University of Glasgow
Vincenzo Corbo: University of Verona

Nature, 2025, vol. 640, issue 8059, 811-820

Abstract: Abstract Intratumour heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance1,2. Oncogene dosage variation contributes to cell-state transitions and phenotypic heterogeneity3, thereby providing a substrate for somatic evolution. Nonetheless, the genetic mechanisms underlying phenotypic heterogeneity are still poorly understood. Here we show that extrachromosomal DNA (ecDNA) is a major source of high-level focal amplification in key oncogenes and a major contributor of MYC heterogeneity in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that ecDNAs drive varying levels of MYC dosage, depending on their regulatory landscape, enabling cancer cells to rapidly and reversibly adapt to microenvironmental changes. In the absence of selective pressure, a high ecDNA copy number imposes a substantial fitness cost on PDAC cells. We also show that MYC dosage affects cell morphology and dependence of cancer cells on stromal niche factors. Our work provides a detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism driving MYC heterogeneity in PDAC.

Date: 2025
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DOI: 10.1038/s41586-025-08721-9

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