The many faces of cancer evolution

Cancer cells acquire genotypic and phenotypic changes over the course of the disease. A minority of these changes enhance cell fitness, allowing a tumor to evolve and overcome environmental constraints and treatment. Cancer evolution is driven by diverse processes governed by different rules, such as discrete and irreversible genetic variants and continuous and reversible plastic reprogramming. In this perspective, we explore the role of cell plasticity in tumor evolution through specific examples. We discuss epigenetic and transcriptional reprogramming in “disease progression” of solid tumors, through the lens of the epithelial-to-mesenchymal transition, and “treatment resistance”, in the context endocrine therapy in hormone-driven cancers. These examples offer a paradigm of the features and challenges of cell plastic evolution, and we investigate how recent technological advances can address these challenges. Cancer evolution is a multi-faceted process, whose understanding and harnessing will require an equally diverse prism of perspectives and approaches.