MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC

• 成果类型: Article
• 署名作者: Fiorini, Elena; Malinova, Antonia; Schreyer, Daniel; Pasini, Davide; Bevere, Michele; Alessio, Giorgia; Rosa, Diego; D'Agosto, Sabrina; Azzolin, Luca; Milite, Salvatore; Andreani, Silvia; Lupo, Francesca; Veghini, Lisa; Grimaldi, Sonia; Pedron, Serena; Castellucci, Monica; Nourse, Craig; Salvia, Roberto; Malleo, Giuseppe; Ruzzenente, Andrea; Guglielmi, Alfredo; Milella, Michele; Lawlor, Rita T.; Luchini, Claudio; Agostini, Antonio; Carbone, Carmine; Pilarsky, Christian; Sottoriva, Andrea; Scarpa, Aldo; Tuveson, David A.; Bailey, Peter; Corbo, Vincenzo
• 署名单位: University of Verona; University of Glasgow; University of Verona; University of Verona; Human Technopole; University of Verona; University of Verona; Beatson Institute; University of Verona; University of Verona; University of Verona; Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli; University of Erlangen Nuremberg; Cold Spring Harbor Laboratory; Human Technopole; University of Wurzburg
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3219
• DOI: 10.1038/s41586-025-08721-9
• 发表日期: 2025-04-17
• 关键词: double minute chromosomes; extrachromosomal dna; tumor; amplification; hydroxyurea; EVOLUTION; subtypes; toolkit; genes

摘要

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.