Phenotypic noise and plasticity in cancer evolution

Cancer cells change phenotype through cancer evolution; some phenotype changes are caused by underlying genetic mutations, but many are due to non-genetic mechanisms.We suggest separating non-genetic phenotype changes into two distinct mechanisms: changes induced by microenvironmental stimuli (that we term ‘phenotypic plasticity’) and changes induced by stochastic cell-intrinsic effects (that we term ‘phenotypic noise’).We discuss how lineage tracing methods – either experimental or those that make use of sporadic mutations to mark lineages – can be used to distinguish between phenotypic plasticity and noise.Distinguishing between phenotypic plasticity and noise guides mechanistic work to determine the molecular causes of phenotype change, and will ultimately accelerate efforts to control or prevent phenotype changes that enable cancer cells to resist therapies. Non-genetic alterations can produce changes in a cell’s phenotype. In cancer, these phenomena can influence a cell’s fitness by conferring access to heritable, beneficial phenotypes. Herein, we argue that current discussions of ‘phenotypic plasticity’ in cancer evolution ignore a salient feature of the original definition: namely, that it occurs in response to an environmental change. We suggest ‘phenotypic noise’ be used to distinguish non-genetic changes in phenotype that occur independently from the environment. We discuss the conceptual and methodological techniques used to identify these phenomena during cancer evolution. We propose that the distinction will guide efforts to define mechanisms of phenotype change, accelerate translational work to manipulate phenotypes through treatment, and, ultimately, improve patient outcomes. Non-genetic alterations can produce changes in a cell’s phenotype. In cancer, these phenomena can influence a cell’s fitness by conferring access to heritable, beneficial phenotypes. Herein, we argue that current discussions of ‘phenotypic plasticity’ in cancer evolution ignore a salient feature of the original definition: namely, that it occurs in response to an environmental change. We suggest ‘phenotypic noise’ be used to distinguish non-genetic changes in phenotype that occur independently from the environment. We discuss the conceptual and methodological techniques used to identify these phenomena during cancer evolution. We propose that the distinction will guide efforts to define mechanisms of phenotype change, accelerate translational work to manipulate phenotyp