意大利维罗纳大学Vincenzo Corbo课题组的研究显示，MYC ecDNA促进PDAC的肿瘤内异质性和可塑性。2025年3月12日出版的《自然》发表了这项成果。

本研究表明，染色体外DNA （ecDNA）是关键癌基因高水平局灶扩增的主要原因，也是胰腺导管腺癌（PDAC）中MYC异质性的主要因素。该研究团队证明了ecDNAs驱动不同水平的MYC剂量，这取决于它们的调控环境，使癌细胞能够快速和可逆地适应微环境变化。在没有选择压力的情况下，高ecDNA拷贝数对PDAC细胞施加了巨大的适应性成本。该课题组还发现MYC剂量影响细胞形态和癌细胞对基质生态位因子的依赖性。他们的工作提供了PDAC中ecdna的详细分析，并描述了驱动PDAC中MYC异质性的新的遗传机制。

据了解，瘤内它们的异质性和表型可塑性驱动肿瘤的进展和治疗耐药性。癌基因剂量变化有助于细胞状态转变和表型异质性，从而为体细胞进化提供了基础。尽管如此，表型异质性的遗传机制仍然知之甚少。

附：英文原文

Title: MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC

Author: Fiorini, Elena, Malinova, Antonia, Schreyer, Daniel, Pasini, Davide, Bevere, Michele, Alessio, Giorgia, Rosa, Diego, DAgosto, 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

Issue&Volume: 2025-03-12

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.

DOI: 10.1038/s41586-025-08721-9

Source: https://www.nature.com/articles/s41586-025-08721-9