It is proposed that understanding and targeting epithelial–mesenchymal plasticity, rather than EMT alone, may provide a more effective framework for precision oncology and metastasis prevention.
Abstract
Epithelial–mesenchymal transition (EMT) is increasingly recognized as a dynamic process of epithelial–mesenchymal plasticity (EMP) rather than a binary switch between epithelial and mesenchymal phenotypes. This plasticity enables tumor cells to acquire invasive, metastatic, stem‐like, and therapy‐resistant characteristics that contribute to cancer progression and poor clinical outcomes. Despite extensive investigation, significant challenges remain in understanding the functional significance of partial EMT states, identifying robust biomarkers that capture EMT heterogeneity, and translating EMT‐targeted interventions into clinical practice. This review critically examines the molecular mechanisms governing EMT, including transcriptional regulators, signaling pathways, epigenetic modifications, and tumor microenvironmental influences. Particular emphasis is placed on hybrid epithelial/mesenchymal states, which have emerged as key drivers of metastatic fitness and therapeutic resistance. We further evaluate established and emerging EMT biomarkers, including E‐cadherin, N‐cadherin, vimentin, circulating tumor cells, and exosome‐derived signatures, highlighting their opportunities and limitations in clinical applications. Finally, we discuss current therapeutic strategies targeting EMT‐associated pathways and explain why many promising preclinical approaches have faced translational barriers. By integrating mechanistic, biomarker, and therapeutic perspectives, this review proposes that understanding and targeting epithelial–mesenchymal plasticity, rather than EMT alone, may provide a more effective framework for precision oncology and metastasis prevention.
Epithelial–mesenchymal transition (EMT) is increasingly recognized as a dynamic, plastic process that equips tumor cells with invasive capacity, stress tolerance, stem-like features, and adaptability, contributing to metastasis, therapeutic failure, and immune escape. Accumulating evidence indicates that these effects can outlast the inducing signal: tumor cells may retain molecular and functional traces of prior EMT exposure, biasing future cell-state behavior. This Review terms this phenomenon EMT memory. We propose EMT memory as a conceptual framework distinguishing it from EMT induction and maintenance through its persistence after signal withdrawal, its capacity to alter future cellular responsiveness, and, in its strongest form, its transmissibility across cell division. DNA methylation and chromatin-state remodeling emerge as the most plausible core substrates, reinforced by histone dynamics, chromatin remodelers, and noncoding RNA networks that stabilize post-EMT states. Temporal concepts including hysteresis, reversibility windows, and partial EMT stabilization clarify when transient plasticity becomes durably encoded, helping explain why highly aggressive tumor cells are often not fully mesenchymal yet remain strongly metastatic, drug tolerant, and immune evasive. We argue that metastatic competence, therapy resistance, and immune evasion can be viewed as functional outputs of remembered plasticity rather than solely as consequences of a contemporaneous mesenchymal phenotype. If transient EMT can be consolidated into persistent adaptive states, therapeutically relevant vulnerabilities may lie not only in EMT-inducing pathways, but also in the mechanisms that encode, reinforce, and preserve EMT memory—positioning memory-bearing states as an important target for future therapeutic strategies.
Tumor plasticity and microenvironmental heterogeneity are established as an integrated, evolving system that fuels metastasis and limits durable treatment responses.
G. Dagar, M. Dagar, Ashna Gupta et al.· MedComm· 0 citations
Summary Cellular plasticity within the tumor microenvironment (TME) extends far beyond classical epithelial-mesenchymal transition (EMT). Emerging evidence indicates that diverse non-epithelial cell populations, including macrophages, endothelial cells, pericytes, adipocytes, and fibroblasts, undergo a progressive and often partial reprogramming toward mesenchymal-like states during tumor progression. We conceptualize this broader phenomenon as mesenchymal drift (MD), a trans-lineage adaptive process characterized by erosion of lineage-specific identity, acquisition of extracellular matrix-remodeling capacity, enhanced migratory potential, and epigenetic stabilization of pro-fibrotic and immunosuppressive programs. In prostate cancer (PCa), MD provides a conceptual framework for interpreting stromal-immune remodeling across epithelial, endothelial, immune, adipose, and fibroblastic compartments. Macrophage-to-myofibroblast transition (MMT), endothelial-to-mesenchymal transition (EndoMT), pericyte-to-fibroblast transition (PFT), and adipocyte mesenchymal transition (AMT) collectively expand the pool of cancer-associated fibroblasts, promote matrix stiffening, induce vascular dysfunction, and reinforce immune evasion. These processes are proposed to be driven by overlapping signaling networks—including TGF-β/Smad, Wnt/β-catenin, Hippo/YAP-TAZ, PDGF, and inflammatory NF-κB/STAT3 pathways—and are stabilized by DNA methylation, histone modifications, and non-coding RNAs. Clinically, MD-associated transcriptional signatures correlate with aggressive phenotypes, metastasis, and therapy resistance across solid tumors, including PCa, highlighting their potential as prognostic biomarkers and therapeutic targets. Pharmacologic inhibition of key MD drivers, epigenetic reprogramming strategies, and combinatorial approaches with immunotherapy represent promising translational avenues. By integrating diverse mesenchymal transition processes under a unified conceptual framework, this review positions mesenchymal drift as a unifying axis of stromal-immune reprogramming in prostate cancer and underscores its significance for next-generation therapeutic strategies.
Zijia Zhang, Feifan Liu, S. Liu et al.· iScience· 0 citations
Epithelial-mesenchymal transition (EMT) is a biological process that involves the transformation of epithelial cells into more mobile and invasive mesenchymal cells. While EMT is crucial for typical physiological functions like maturation of the embryo and tissue restoration, its association with cancer often leads to tumor proliferation, metastasis, and resistance to therapy. This transition permits tumors to acquire traits that promote invasion, migration, and resistance to cell death. Therefore, unraveling the intricate mechanisms of EMT activation in cancer will contribute to the advancement of personalized medicine and the design of more effective treatments against metastatic disease. Inhibiting EMT holds the potential for restricting cancer cell invasion and metastasis, ultimately improving patient outcomes. EMT induction can be triggered by various factors, including extracellular signals, external substances, and pathological conditions such as hypoxia. This paper primarily examines the function of EMT in the initiation and progression of tumors, along with the factors that contribute to its activation. With the aid of cutting-edge technologies and improved experimental techniques, researchers can more effectively investigate the complex network of molecular events underlying EMT, leading to the identification of novel biomarkers and the advancement of therapies. By leveraging these advancements, scientists are better equipped to unravel the intricacies of EMT and pave the way for advancements in personalized medicine and improved treatment strategies for patients affected by EMT-related conditions. Understanding the cellular events and signaling cascades that drive EMT can aid in the development of interventions that disrupt or reverse this process.
Vafa Meftahpour, T. C. Dakal, Jarek Maciaczyk et al.· Signal Transduction and Targ...· 0 citations
Colorectal cancer (CRC) progression and metastasis, as well as tolerance to therapy, are driven not only by genetic alterations but also by cell-state plasticity. Oncofetal reprogramming (OnF) refers to the reactivation of fetal intestinal developmental or injury-repair programs in tumor cells, thereby weakening adult lineage identity and enhancing the capacity for state transitions. Available evidence suggests that, in specific Wnt-dependent or APC-aberrant contexts, YAP/TAZ–TEAD and AP-1 may act cooperatively to establish and maintain the OnF state, whereas Wnt, EGFR–MAPK, FGF/FGFR, TGF-β, and extracellular matrix signaling contribute to its establishment and maintenance in a context-dependent manner. The OnF state can also intersect with epithelial–mesenchymal plasticity, dynamic stemness, drug-tolerant persister states, and immune and stromal niches, collectively increasing cellular heterogeneity, adaptability to therapy, and relapse potential in CRC. This review discusses the conceptual boundaries and operational criteria for identifying OnF in CRC, examines its regulatory mechanisms, plasticity-associated phenotypes, and translational relevance, and emphasizes the importance of distinguishing direct evidence of OnF from evidence of related plasticity mechanisms. Further elucidation of the OnF state may facilitate biomarker development and anti-plasticity therapies, although its clinical translation will require standardized state classification and clinical validation.
Haoyu Wang, Songhao Liu, Ming-Xuan Zhang et al.· Frontiers in Oncology· 0 citations
Summary Epithelial-mesenchymal transition (EMT) is a reversible cellular program that allows epithelium-derived cells to acquire mesenchymal phenotypes, whereas mesenchymal-epithelial transition (MET) enables mesenchymal cells to regain epithelial properties. The capacity for EMT and MET, known as epithelial-mesenchymal plasticity (EMP), represents an indispensable mechanism of invasive plasticity for tumor progression during the spatiotemporal invasion-metastasis cascade. In this review, we elucidate the pivotal role of EMP in tumor metastasis and treatment resistance, as well as the latest understanding of the molecular mechanisms that regulate this cellular characteristic. We further summarize the methodology and technology for evaluating EMP and discuss the clinical translational potential of targeting EMP-related signaling pathways as a personalized anti-metastasis therapeutic strategy.