Paul Mischel is a physician scientist trained in pathology and cancer biology. He has made a series of discoveries that have identified a central role for ecDNA (extrachromosomal DNA) in cancer development, progression, accelerated tumor evolution and drug resistance. These findings have provided a new understanding of the fundamental mechanisms of oncogene amplification and the spatial organization of altered tumor genomes, launching a new area of cancer research that links circular architecture with tumor pathogenesis. His team has developed and applied a set of state of the art genetic, biochemical, computational, and advanced cell imaging tools to decipher the structure of circular ecDNA in cancer to a well-curated, large set of deeply characterized, ecDNA+ cancer models, revealing enhanced chromatin accessibility and the physical formation of new cis-regulatory interactions that lead to massive oncogene transcription and tumor progression. His lab has also uncovered metabolic co-dependencies that are downstream consequences of oncogene amplification. These include a central role for altered biochemical mechanisms that regulate oncogene copy number and function. These discoveries have resulted in new understandings of some of the fundamental processes by which oncogene amplification drives cancer progression and drug resistance in the changing environments within which tumors develop