Closing the Circle: New Tools to Decode the Biology of Extrachromosomal Amplification

Discovered more than half a century ago, extrachromosomal DNA (ecDNA) has recently been recast as one of the most prevalent and consequential mechanisms of oncogene amplification in human cancer, with profound implications on how we think about intratumoral heterogeneity, tumor evolution, and therapeutic resistance. Here we highlight the unique features of ecDNA-mediated gene amplification and their implications for cancer biology. Finally, we provide an overview of emerging strategies to engineer ecDNA de novo and model its biology in experimentally tractable systems, with the goal of developing more faithful preclinical models in which the vulnerabilities imposed by ecDNA can be defined and tested.