Aug 2026· Signal Transduction and Targeted Therapy· Vol 11· 0 citations· 401 references
Medicine
TL;DR
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 and pave the way for advancements in personalized medicine and improved treatment strategies for patients affected by EMT-related conditions.
Abstract
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.
The pivotal role of EMP in tumor metastasis and treatment resistance is elucidated and the clinical translational potential of targeting EMP-related signaling pathways as a personalized anti-metastasis therapeutic strategy is discussed.
The clinical translation of EMT-directed interventions faces steep methodological hurdles, primarily driven by unverified causal dynamics and unresolved therapeutic safety profiles, and will require dynamic, multi-pronged strategies tailored to specific carcinoma cell states and spatial niches.
Xuecong Wang, C. Zhang, Yi Zhao et al.· Cancer Metastasis Review· 0 citations
Epithelial-mesenchymal transition (EMT) is a dynamic process that contributes to breast cancer progression, metastasis, and therapy resistance. EMT also influences the tumor immune microenvironment, shaping immune cell infiltration and function. Although the immunological features of fully epithelial or fully mesenchymal tumor states have been characterized, the immune landscape associated with intermediate or partial EMT states remains poorly understood. To examine the relationship between EMT progression and immune cell composition and function, we established five single-cell–derived clonal populations from the triple-negative 4T1 mouse mammary tumor cell line, representing a spectrum of EMT phenotypes, and analyzed tumors derived from these clones using single-cell RNA sequencing. Tumors derived from these clones retained their relative EMT states in vivo, and EMT progression was associated with a graded reduction in tumor immunogenicity, accompanied by alterations in immune cell composition and function. Along the EMT spectrum, tumor cells exhibited progressive downregulation of major histocompatibility complex (MHC) class I and II gene expression, along with decreased infiltration of cytotoxic CD8+ T cells and reduced expression of key effector and trafficking genes (Gzmb, Ccr5, Cxcr6). B cell composition also shifted, with decreased frequencies of IgG1-producing plasma cells and an enrichment of regulatory-like B cells. Natural killer (NK) cells similarly demonstrated progressive functional suppression, marked by reduced expression of cytotoxic molecules and the downregulation of specific effector pathways. These findings reveal that EMT is associated with immune cell recruitment and function in a graded manner, providing a rationale for integrating EMT phenotyping into therapeutic strategies to overcome immune resistance in breast cancer.
Han-Xu Lu, Meisam Bagheri, F. Kolling et al.· Breast Cancer Research· 0 citations
The ability of cancer cells to transition between epithelial and mesenchymal states, a process known as epithelial-to-mesenchymal transition (EMT), is a key driver of cancer metastasis and therapy resistance. While ataxia telangiectasia and Rad3-related (ATR) kinase was originally characterized as a responder to DNA damage and replication stress, recent discoveries implicate a critical role for ATR in EMT and metastasis. Two pivotal studies published in this issue of JCI provide key insights into how ATR intersects with EMT transcriptional reprogramming. Patel et al. demonstrated that ATR prevented R-loop accumulation at EMT-related gene loci, thereby facilitating the transcriptional reprogramming necessary for EMT as well as tumor growth and metastasis. Tu et al. further uncovered a role for ATR in ECM stiffness–induced EMT, which was associated with an immunosuppressive tumor microenvironment. Together, these studies highlight important therapeutic implications for ATR targeting in the context of metastasis and therapy resistance.
The conceptual boundaries and operational criteria for identifying OnF in CRC are discussed, its regulatory mechanisms, plasticity-associated phenotypes, and translational relevance are examined, and the importance of distinguishing direct evidence of OnF from evidence of related plasticity mechanisms is emphasized.
Hao-Yu Wang, Song-Hao Liu, Ming-Xuan Zhang et al.· Frontiers in Oncology· 0 citations
Bladder cancer (BLCA) is a common and heterogeneous malignancy in which disease progression is driven not only by tumor-intrinsic alterations but also by dynamic interactions within the tumor microenvironment (TME). Increasing evidence positions the extracellular matrix (ECM) as a critical regulator of these processes. Matricellular proteins (MCPs), a group of nonstructural ECM-associated molecules, have emerged as key modulators of tumor–stroma communication. In BLCA, MCPs have been reported to display divergent, and in some cases opposing, associations or functions, with the same protein participating in both tumor promotion and suppression. Here, we review current evidence on the function of MCPs in BLCA and synthesize their bidirectional roles in carcinogenesis. MCPs contribute to tumor progression by promoting invasion, epithelial–mesenchymal transition (EMT), angiogenesis, and metastatic niche formation. At the same time, MCPs can restrain tumor growth by inhibiting angiogenesis, stabilizing ECM organization, inducing cell cycle arrest, and maintaining epithelial integrity. A key concept emerging from this body of evidence is the context-dependent functional plasticity of MCPs. We propose that MCP-associated phenotypes in BLCA may be influenced by contextual factors, including isoform diversity arising from alternative splicing and post-translational modifications, spatial compartmentalization within tumor and stromal niches, tumor microenvironmental composition, and molecular subtype. However, the level of supporting evidence differs substantially among MCPs, and direct BLCA-specific mechanistic evidence remains limited for many proposed relationships. These factors, therefore, provide a framework for interpreting divergent findings rather than representing universally established determinants of MCP function. Recognizing MCPs as context-sensitive regulators rather than fixed tumor-promoting or tumor-suppressing entities provides a unifying framework for understanding their roles in BLCA. This could be an important step for therapeutic targeting, encouraging effective strategies to consider and incorporate the molecular and microenvironmental context in which MCPs operate.
Azamat Akhmetkaliyev, José Héctor Gibrán Fritz García, E. Sonnenberg-Riethmacher et al.· International Journal of Mol...· 0 citations
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