Hallmarks of epithelial-mesenchymal plasticity in cancer

Cancer stem cells (CSCs) drive tumour initiation, progression, metastasis, and therapy resistance through their remarkable plasticity, enabling dynamic transitions between stem-like and differentiated states. A pivotal mechanism underlying this plasticity is epithelial-mesenchymal plasticity (EMP), which encompasses epithelial-mesenchymal transition (EMT), partial or hybrid EMT (E/M) states, and mesenchymal-epithelial transition (MET), allowing cancer cells to acquire invasive, stem-like properties while maintaining proliferative potential. Unlike the traditional binary view of EMT, recent evidence reveals a spectrum of intermediate E/M phenotypes that exhibit increased tumorigenicity, metastatic potential, and therapy resistance. This plasticity is orchestrated by intricate regulatory networks involving EMT-inducing transcription factors, signalling pathways, and non-coding RNAs. The tumour microenvironment (TME), with its cellular and non-cellular components, provides critical extrinsic cues that stabilize E/M states. Notably, metabolic reprogramming cooperates with EMP. Indeed, E/M flexibly shifts between glycolysis, oxidative phosphorylation, and lipid metabolism alterations to fuel invasion, buffer oxidative stress, and evade ferroptosis. Advanced and recently developed in vitro and in vivo models have illuminated these dynamics: dual-fluorescent reporters, microfluidic tumour-on-a-chip, genetically engineered mouse models, bioluminescence imaging, and intravital microscopy enable real-time tracking of EMP during progression and therapy response. On the other side, in silico tools, single-cell/spatial transcriptomics, network inference, machine learning, and agent-based modelling, map hybrid states, predict trajectories, and help identify biomarkers, revealing EMP's role in evolutionary fitness. Therapeutically, targeting EMP holds promise to target resistant cancer cells and prevent relapse, though challenges arise from redundancy and plasticity. Strategies include pathway inhibitors, metabolic disruptors, epigenetic agents, TME modulators, and differentiation inducers. Combination therapies, guided by EMP biomarkers and rational models, act in combination with standard treatments to lock cells in epithelial states, disrupt hybrid phenotypes, and overcome resistance. This review highlights EMP as the main driver of tumour evolution, offering a unified framework for understanding tumour heterogeneity and heterogeneity-driven failures in therapy. By elucidating molecular mechanisms and vulnerabilities, it paves the way for precision interventions that could transform outcomes in aggressive malignancies, ultimately restraining metastasis and recurrence.