Drug tolerance and persistence in bacteria, fungi and cancer cells: Role of non-genetic heterogeneity

Abstract

• Non-genetic cellular heterogeneity drives persisters in bacteria, fungi, and cancer. • Gene expression variability is a fundamental feature enabling persister formation. • Persisters act as precursors for genetic adaptation under high-stress conditions. A common feature of bacterial, fungal and cancer cell populations upon treatment is the presence of tolerant and persistent cells able to survive, and sometimes grow, even in the presence of usually inhibitory or lethal drug concentrations, driven by non-genetic differences among individual cells in a population. Here we review and compare data obtained on drug survival in bacteria, fungi and cancer cells to unravel common characteristics and cellular pathways, and to point their singularities. This comparative work also allows to cross-fertilize ideas across fields. We particularly focus on the role of gene expression variability in the emergence of cell-cell non-genetic heterogeneity because it represents a possible common basic molecular process at the origin of most persistence phenomena and could be monitored and tuned to help improve therapeutic interventions.