Phenotypic plasticity, the capacity of cells to transition between distinct phenotypic and lineage states over time, is a genetically and epigenetically encoded trait essential for normal development and adult tissue homeostasis. In cancer, phenotypic plasticity programs can be deployed aberrantly to enable disease progression and acquired therapeutic resistance. Cancer phenotypic plasticity is a current barrier to achieving cures for advanced cancers using available molecularly targeted therapies. This review summarizes the complex and interconnected molecular pathways implicated in phenotypic plasticity, both in the context of normal tissue homeostasis and cancer. Molecular pathways convergent between these contexts are highlighted while pathways enabling plasticity are distinguished from those that specify the phenotype of already plastic cells. Key unresolved questions in the field are discussed along with emerging technologies that may be used to help answer them.

cancer, plasticity, heterogeneity, epigenetics, homeostasis, therapeutic resistance