Implications of non-genetic heterogeneity in cancer drug resistance and malignant progression

Abstract Nongenetic heterogeneity in cancer plays a critical role in disease progression and response to therapy. While variability in cellular phenotypes results from both gene expression noise and different stable phenotypic states, in this chapter we will focus on theory and evidence for nongenetic heterogeneity due to phenotypic plasticity of cancer cells. To elucidate the theory that allows for heterogeneous populations of cells regardless of the genomic state, we incorporate the concept of the phenotypic landscape—in which cells reside in stable “attractor” states. Cells have the ability to transition to different states, and the probability of these transitions may be in part dependent on environmental conditions and independent of the genome. Mathematical models allow us to build a simplified understanding of heterogeneous states and the transition rates between states within a cancer cell population. Here we discuss ways that cell states are identified and measured to investigate nongenetic heterogeneity in various empirical settings. For example, we describe one of the most well-characterized cell state transitions, the epithelial-to-mesenchymal transition (EMT) observed in cancer cells in response to environmental cues. Because EMT is a physiological process in development and tissue repair, the accompanying cell state transitions are well defined and can be confirmed by multiple readouts. Additionally, we describe instances of nongenetic heterogeneity and phenotypic state switching defined by other cell states with functional relevance to cancer progression and drug response. To make progress in preventing the seemingly inexorable onset of chemoresistance, it is necessary to elucidate how drug exposure directly induces cell state transitions between sensitive and resistant cell states. We discuss here the evidence that exposure to cytotoxic or targeted therapeutic treatments may cause cells to activate transcriptional or cell signaling programs that render them insensitive to treatment via a variety of different resistance mechanisms.