ecDNA amplification of MYC drives intratumor copy-number heterogeneity and adaptation to stress in PDAC

Intratumor heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance. Oncogene dosage variation contributes to cell state transitions and phenotypic heterogeneity, 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 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 the first detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism driving MYC heterogeneity in PDAC.肿瘤内异质性与表型可塑性可推动肿瘤进展与治疗耐受。致癌基因剂量变异可介导细胞状态转换与表型异质性的产生，进而为体细胞进化提供底物基础。然而，介导表型异质性形成的遗传机制仍未得到充分阐释。本研究证实，染色体外DNA（extrachromosomal DNA, ecDNA）是关键致癌基因发生高水平局域扩增的核心来源，同时也是胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）中MYC异质性的重要驱动因素。我们发现，ecDNA可依据自身的调控景观调控不同水平的MYC基因剂量，使癌细胞能够快速且可逆地适应微环境的变化。在无选择压力的条件下，高拷贝数的ecDNA会对胰腺导管腺癌细胞施加显著的适合度成本。本研究同时证实，MYC基因剂量可影响癌细胞的形态以及其对基质微环境因子的依赖性。本研究首次针对胰腺导管腺癌中的ecDNA开展了系统性详细分析，并揭示了驱动胰腺导管腺癌中MYC异质性形成的全新遗传机制。