MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC
Intratumour heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance<sup>1,2</sup>. Oncogene dosage variation contributes to cell-state transitions and phenotypic heterogeneity<sup>3</sup>, 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.
Authors
- Aldo Scarpa
- Carmine Carbone (ORCID: https://orcid.org/0000-0001-5168-747X)
- Monica Castellucci
- Serena Pedron
- Christian Pilarsky (ORCID: https://orcid.org/0000-0002-7968-3283)
- Andrea Ruzzenente (ORCID: https://orcid.org/0000-0001-6911-563X)
- Michèle Milella (ORCID: https://orcid.org/0000-0002-3826-5237)
- Vincenzo Corbo (ORCID: https://orcid.org/0000-0002-6340-8009)
- Giuseppe Malleo (ORCID: https://orcid.org/0000-0001-5467-2628)
- Daniel Schreyer (ORCID: https://orcid.org/0000-0002-9788-0168)
- Sabrina D’Agosto (ORCID: https://orcid.org/0000-0003-0950-9914)
- Sonia Grimaldi (ORCID: https://orcid.org/0000-0002-3675-3560)
- Andrea Sottoriva (ORCID: https://orcid.org/0000-0001-6709-9533)
- Rita T. Lawlor (ORCID: https://orcid.org/0000-0003-3160-0634)
- Claudio Luchini (ORCID: https://orcid.org/0000-0003-4901-4908)
- Davide Pasini (ORCID: https://orcid.org/0000-0002-8270-7143)
- Antonia Malinova (ORCID: https://orcid.org/0000-0003-0325-501X)
- Luca Azzolin (ORCID: https://orcid.org/0000-0002-2919-4617)
- Salvatore Milite (ORCID: https://orcid.org/0000-0002-0156-3636)
- Elena Fiorini (ORCID: https://orcid.org/0000-0002-9693-6094)
- Lisa Veghini (ORCID: https://orcid.org/0000-0003-3289-1189)
- Silvia Andreani (ORCID: https://orcid.org/0000-0002-3715-1553)
- Roberto Salvia (ORCID: https://orcid.org/0000-0002-3514-8473)
- David A. Tuveson (ORCID: https://orcid.org/0000-0002-8017-2712)
- Alfredo Guglielmi (ORCID: https://orcid.org/0000-0003-1713-4307)
- Craig Nourse
- Michele Bevere (ORCID: https://orcid.org/0000-0001-8778-0860)
- Antonio Agostini (ORCID: https://orcid.org/0000-0002-6528-7140)
- Peter J. Bailey (ORCID: https://orcid.org/0000-0002-0857-2041)
- D.D. Rosa
- Francesca Lupo
- Giorgia Alessio
Institutions
- Champalimaud Foundation (PT)
- University of Verona (IT)
- University of Würzburg (DE)
- Cold Spring Harbor Laboratory (US)
- Agostino Gemelli University Polyclinic (IT)
- Universitätsklinikum Erlangen (DE)
- Human Technopole (IT)
- Cancer Research UK Scotland Institute (GB)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Glasgow (GB)
Publication Details
- Journal
- Nature
- Published
- 2025-03-12
- DOI
- https://doi.org/10.1038/s41586-025-08721-9
- Citations
- 32
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 25.79