MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC

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 (March 2025) MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC. Nature. ISSN 0028-0836 (Public Dataset)

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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.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
diseases & disorders > cancer > cancer types > pancreatic cancer
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Tuveson lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 12 March 2025
Date Deposited: 14 Mar 2025 18:43
Last Modified: 14 Mar 2025 18:43
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Dataset ID:
URI: https://repository.cshl.edu/id/eprint/41817

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