Reconciling Non-Genetic Plasticity with Somatic Evolution in Cancer

Post-treatment progression of tumors is commonly explained by somatic Darwinian evolution (i.e., selection of cells carrying genetic mutations that create more aggressive cell traits). But cancer genome and transcriptome analyses now paint a picture far more complex, prompting us to see beyond the Darwinian scheme: non-genetic cell phenotype plasticity explained by alternative stable gene expression states ('attractors'), may also produce aggressive phenotypes that can be selected for, without mutations. Worse, treatment may even induce cell state transitions into more malignant attractors. We review recent evidence for non-genetic mechanisms of progression, explain the theoretical foundation of attractor transitions behind treatment-induced increase of aggressiveness, and provide a framework for unifying genetic and non-genetic dynamics in tumor progression.