Perturbation-Driven Entropy as a Source of Cancer Cell Heterogeneity

Mutations, aberrant epigenetic changes, and other perturbations increase the stochasticity of gene regulatory networks, increasing entropy. Increased entropy can be the result of nongenomic changes in the transcriptional networks and is thus at least partially reversible. Both driver and passenger mutations can contribute to increased gene regulatory network entropy. At the single-cell level, perturbation-driven entropy increases plasticity; at the population level, an increase in network entropy results in increased heterogeneity. Perturbation-driven entropy can contribute to cancer evolvability and therapeutic resistance. Intratumor heterogeneity is a key hallmark of cancer that contributes to progression and therapeutic resistance. Phenotypic heterogeneity is in part caused by Darwinian selection of subclones that arise by random (epi)genetic aberrations. In addition, cancer cells are endowed with increased cellular plasticity compared with their normal counterparts, further adding to their heterogeneous behavior. However, the molecular mechanisms underpinning cancer cell plasticity are incompletely understood. Here, I outline the hypothesis that cancer-associated perturbations collectively disrupt normal gene regulatory networks (GRNs) by increasing their entropy. Importantly, in this model both somatic driver and passenger alterations contribute to 'perturbation-driven entropy', thereby increasing phenotypic heterogeneity and evolvability. This additional layer of heterogeneity may contribute to our understanding of cancer evolution and therapeutic resistance. Intratumor heterogeneity is a key hallmark of cancer that contributes to progression and therapeutic resistance. Phenotypic heterogeneity is in part caused by Darwinian selection of subclones that arise by random (epi)genetic aberrations. In addition, cancer cells are endowed with increased cellular plasticity compared with their normal counterparts, further adding to their heterogeneous behavior. However, the molecular mechanisms underpinning cancer cell plasticity are incompletely understood. Here, I outline the hypothesis that cancer-associated perturbations collectively disrupt normal gene regulatory networks (GRNs) by increasing their entropy. Importantly, in this model both somatic driver and passenger alterations contribute to 'perturbation-driven entropy', thereby increasing phenotypic heterogeneity and evolvability. This additional layer of heterogeneity may contribute to our understanding of cancer evolution and therapeutic resistance.