CancerPersisters · Understanding and targeting cancer persister cells

Despite tremendous progress in cancer therapy, many patients still succumb to the disease following an initial successful response to treatment. In addition to the long-appreciated contribution of genetically mutated cells to disease recurrence, persister cells, a rare subpopulation of cells that evade therapy in the absence of any known resistance-mediating mutation, have recently emerged as orthogonal drivers of therapy failure. While there has been much progress in targeting genetic resistance, the paucity of molecular tools that can capture persister traits, as well as the lack of a robust methodological framework for their study have significantly hampered our understanding and ability to target persister cells. Nevertheless, recent breakthroughs in molecular profiling techniques, as well as growing access to human residual disease clinical samples, now provide the opportunity to uncover the molecular underpinnings of this crucial cellular state. In this project, I propose to combine state-of-the-art single-cell lineage tracing techniques with functional approaches to (1) identify the determinants that control the ability of persister cells to escape therapy-induced senescence; (2) elucidate the cellular processes that govern the duration of persister drug-induced arrest; (3) investigate how epigenetic memory shapes persisters response to subsequent cycles of therapy. CancerPersisters will establish the tools that are needed in order to study key persister traits and further our understanding of this important cancer phenotype. Successful completion of this project may instruct the development of new classes of cancer drugs that can resensitize patients to subsequent cycles of therapy by erasing cellular memory and increase progression-free survival by modulating the duration of drug-induced arrest.