More than fifty years ago, extrachromosomal circular DNAs (ecDNAs) known as “Double Minutes” were identified as common features in aggressive human cancers. These large extrachromosomal elements have the ability to unevenly segregate into daughter cells, contributing to intra-tumoral heterogeneity and potentially facilitating oncogene amplification and tumor evolution. Despite growing interest in these cancer-associated genetic lesions, many aspects of their formation, maintenance, replication, and role in tumor initiation and progression remain poorly understood. Progress in this field has been hindered by the lack of effective methods to engineer specific ecDNAs in vitro and in vivo, leading most studies to rely on established cancer cell lines with naturally occurring ecDNAs.
In this ASPIRE award, Andrea Ventura aims to overcome these challenges by employing an innovative strategy developed by his team to engineer gene amplifications mediated by ecDNAs in cell lines and in vivo. The research will focus on genetically engineered mouse strains containing inducible ecDNAs harboring oncogenes commonly found in human ecDNAs: EGFR, MYC, or MDM2. The research group will first study whether formation of oncogene-containing ecDNAs ex vivo is sufficient to induce cellular transformation. Subsequently, they will explore whether the generation of oncogenic ecDNAs in mice can initiate tumor formation either independently or in conjunction with other genetic events. Finally, the contribution of ecDNAs to tumor progression and metastasis will be examined in vivo. Successful completion of these experiments will provide significant insights into this crucial class of cancer-associated genetic elements, advancing our understanding of ecDNAs and potentially unveiling novel therapeutic strategies tailored to target ecDNA-containing cancers.