Epithelial-mesenchymal transition in carcinoma: navigating phenotypic states to target resistance and metastasis

Epithelial-mesenchymal transition (EMT), historically described as a binary morphological change from an epithelium to a mesenchymal state, no longer adequately accounts for carcinoma cell phenotypes observed in patients. Single-cell sequencing, spatial-omics, and lineage tracing converge on a different picture as carcinoma cells rarely undergo a unidirectional transition ending as sarcoma-like cells. Instead, carcinoma cells distribute across a continuum of intermediate states in which partial EMT often as hybrid epithelial/mesenchymal phenotypes couple adhesion and survival to motility, stress tolerance, and adaptive reprogramming. While EMT signatures remain a recurrent hallmark of metastasis, treatment failure, and disease relapse in epithelial cancers, functional cell plasticity is fundamentally shaped by distinct histotypes, tumor stages, malignancy grades, and local microenvironmental ecosystems. Carcinoma cells may not need to acquire a fixed position in the EMT spectrum to invade and metastasize, and "more mesenchymal" does not necessarily translate to "more dangerous." The clinical translation of EMT-directed interventions faces steep methodological hurdles, primarily driven by unverified causal dynamics and unresolved therapeutic safety profiles. Overcoming these hurdles will require dynamic, multi-pronged strategies tailored to specific carcinoma cell states and spatial niches. Effective regimens must simultaneously deploy oncogene inhibition, state-plasticity restriction, and microenvironmental, metabolic, or extracellular matrix-directed remodeling.