Xi Wei†
Wei Li
Tao Li- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
Prostate cancer (PCa) is the most prevalent cancer in men and the fifth leading cause of cancer-related mortality among men globally. Despite substantial advancements in patient prognosis attributable to improvements in PCa treatment, individuals with metastatic castration-resistant prostate cancer continue to experience poor outcomes. Epithelial-mesenchymal transition (EMT) is characterized as a cellular event in which epithelial cells adopt a mesenchymal phenotype while simultaneously losing their epithelial characteristics. EMT has been demonstrated to be associated with the progression of PCa, encompassing tumor metastasis, recurrence, drug resistance, and the development of an immunosuppressive microenvironment. Consequently, this review synthesizes recent studies on EMT in PCa, consolidating the events mediated by EMT in the progression of PCa and the molecular mechanisms linked to EMT activation in this context.
Introduction
PCa is the most prevalent malignant tumor of the male genitourinary system, ranking second in incidence and fifth in mortality among malignant tumors in men globally (Siegel et al., 2023). Treatment strategies for PCa typically depend on factors including prostate-specific antigen levels, pathological type, Gleason score, and clinical stage (Teo et al., 2019; Gillessen et al., 2023). For early-stage (T1 and T2) PCa, favorable outcomes can be attained through active surveillance, local radiotherapy, or radical prostatectomy (Teo et al., 2019; Gillessen et al., 2023). However, due to the extended latent period of PCa, approximately 70% of PCa cases are either locally advanced or widely metastatic at the time of diagnosis. Treatment for advanced PCa primarily relies on androgen deprivation therapy, radiochemotherapy, and targeted therapies (Falagario et al., 2023; Preisser et al., 2024). Although these treatments initially yield favorable results, resistance inevitably develops, resulting in the progression to castration-resistant prostate cancer (CRPC). Once CRPC manifests, current drugs and treatment methods frequently fail to yield effective outcomes (Falagario et al., 2023; Preisser et al., 2024). Notably, mounting evidence suggests that EMT plays a crucial role in the progression of PCa, encompassing recurrence, drug resistance, metastasis, and the development of CRPC (Dunning et al., 2011; Teng et al., 2021). Thus, understanding the cellular and molecular mechanisms, including EMT, involved in PCa progression could offer potential therapeutic strategies to mitigate PCa-related mortality.
EMT is recognized as a fundamental mechanism in cancer metastasis (Haffner et al., 2021; Cha et al., 2020). Emerging evidence indicates that EMT is not only closely associated with tumor metastasis but also with tumor stemness, cytokine release, cancer-associated angiogenesis, immune evasion, and chemoresistance (Pan et al., 2021; Lambert and Weinberg, 2021). Consequently, EMT is widely acknowledged as a hallmark of cancer and is considered a potential contributor to mortality in most solid tumors, including PCa. Notably, extensive evidence supports that EMT is associated not only with the metastatic and disseminative capabilities of PCa but also with the development of CRPC. It has been reported to exhibit significant cross-talk with the androgen receptor (AR) signaling pathway (Dunning et al., 2011; Teng et al., 2021). Recent advances in single-cell RNA sequencing (scRNA-seq) have shed new light on the biological role of EMT in PCa (He et al., 2024). Analyses of metastatic PCa single-cell atlases have identified four functional EMT subtypes: classical mesenchymal, inflammatory, metabolic adaptive, and stem cell-like (He et al., 2024; Jia et al., 2025). Notably, the stem cell-like subtype (CD44+) is highly enriched in CRPC and exhibits significantly reduced sensitivity to androgen receptor (AR) inhibitors (He et al., 2024; Jia et al., 2025; Baumeister et al., 2021). While single-cell sequencing offers novel insights into EMT heterogeneity, its clinical translation remains challenging. A systematic exploration of EMT’s core mechanisms, regulatory networks, and heterogeneity—integrated with spatial transcriptomic approaches—will advance our understanding of PCa progression and provide critical theoretical foundations for optimizing precision therapies and risk stratification.
Overview of EMT
EMT is defined as a cellular event in which epithelial cells acquire a mesenchymal phenotype while losing their epithelial characteristics (Haffner et al., 2021). This process is frequently observed in embryonic development, wound healing, organ fibrosis, and tumor metastasis (Cha et al., 2020). EMT, in conjunction with mesenchymal-epithelial transition (MET), plays a critical role in both early and late stages of embryonic development, including implantation, gastrulation, and heart formation (Pan et al., 2021). EMT is linked to various tumor functions, including tumor initiation, malignant progression, tumor stemness, cell migration, metastasis, and treatment resistance, and is often excessively activated in cancer cells (Haffner et al., 2021; Cha et al., 2020; Pan et al., 2021; Lambert and Weinberg, 2021). The hallmark characteristics of EMT involve epithelial cells gradually losing adhesion molecules such as E-cadherin and β-catenin, along with tight junction proteins. This process is accompanied by the expression of mesenchymal markers, including N-cadherin, R-cadherin, and vimentin, as well as increased levels of extracellular matrix and focal adhesion proteins (Pastushenko and Blanpain, 2019; Akhmetkaliyev et al., 2023). When tumor epithelial cells undergo EMT, their cell polarity and adhesion capabilities diminish, and they acquire a mesenchymal cell phenotype that promotes metastasis and drug resistance (Akhmetkaliyev et al., 2023). EMT is regulated by a series of transcription factors, primarily comprising Snail transcription factors, basic Helix-loop-helix (bHLH) proteins, and Zinc finger E-box binding homeobox (ZEB) transcription factors (Singh et al., 2018). EMT is also reported to be associated with, and regulated by, various oncogenic pathways, including Transforming Growth Factor-β (TGF-β), Wnt, and Notch signaling pathways. These pathways activate the aforementioned transcription factors, inhibiting the expression of E-cadherin and promoting the acquisition of a mesenchymal phenotype in tumor cells (Saitoh, 2023).
EMT and progression in PCa
EMT and metastasis in PCa
Since metastasis is the leading cause of cancer-related deaths in malignant tumors, developing targeted therapeutic strategies to inhibit cancer metastasis is crucial (Valastyan and Weinberg, 2011). EMT is typically associated with tumor metastasis and is recognized as a primary driver of this process. Mechanistically, following the EMT, epithelial cells acquire distinct mesenchymal characteristics (such as diminished cell polarity and adhesion), enabling them to invade the extracellular matrix as individual cells, thus marking the initial stage of tumor metastasis (Pastushenko and Blanpain, 2019; Akhmetkaliyev et al., 2023). Subsequently, these cells detach further from the primary tumor, enter the bloodstream, and colonize distant tissues, proliferating and initiating metastasis, indicating that tumor metastasis relies on the EMT process (Pastushenko and Blanpain, 2019; Akhmetkaliyev et al., 2023; Singh et al., 2018; Saitoh, 2023; Valastyan and Weinberg, 2011; Lu et al., 2022). This phenomenon has been observed in various tumors, including PCa. Previous studies have demonstrated that circulating PCa cells obtained from the blood of PCa patients exhibit upregulated expression of EMT-related genes (Pal et al., 2015), and these circulating tumor cells display a heightened mesenchymal phenotype (Pal et al., 2015). Similarly, clinical specimens from PCa patients have confirmed that metastatic tissues exhibit elevated levels of EMT-related genes and a more pronounced mesenchymal phenotype compared to primary tissues (Parol et al., 2021).
EMT and metabolic traits in PCa
During EMT, PCa cells undergo marked metabolic reprogramming, endowing mesenchymal-like cells with unique adaptations that enhance survival and drive therapeutic resistance (Du et al., 2022). Recent studies reveal that mesenchymal-like PCa cells rely on glycolysis via the Warburg effect (Fontana et al., 2023), with single-cell metabolomics demonstrating a twofold increase in glycolytic flux compared to epithelial cells (Zhang Z. et al., 2023). Key regulators include HIF-1α-driven overexpression of GLUT1 and LDHA, alongside elevated PKM2 dimers that boost lactate production (Icard et al., 2022). Lactate excretion lowers tumor microenvironment pH, sustaining mesenchymal phenotypes through TGF-β signaling while suppressing CD8+ T cell activity to promote immune evasion (Kao et al., 2022). These cells also exhibit heightened glutamine dependence, with GLS1 expression increasing over fourfold (Du et al., 2022). Glutamine breakdown generates α-ketoglutarate (α-KG) to replenish the TCA cycle (Du and Hu, 2021), and ZEB1 reinforces this process by repressing miR-203, forming a positive feedback loop that upregulates GLS1 (Zhao et al., 2020). Glutamine-derived purines further support DNA repair under chemotherapy-induced stress, enhancing cell survival (Zhou et al., 2020). Mesenchymal-like PCa cells coordinately enhance fatty acid oxidation (FAO) and synthesis (FAS) (Tan et al., 2023). Single-cell lipidomics show upregulated CPT1A, which shuttles fatty acids into mitochondria for β-oxidation (Meng et al., 2024), while ACC phosphorylation inactivates FAS to relieve FAO suppression (Carroll et al., 2020). Concurrently, SREBP1-mediated lipid synthase expression increases membrane fluidity to facilitate migration (Du et al., 2022).
Epigenetic effects of EMT on PCa
Emerging studies highlight the pivotal role of epigenetic modifications in PCa metastasis and therapy resistance by dynamically regulating EMT plasticity (Tan et al., 2022). The epigenetic network—comprising DNA methylation, histone modifications, and non-coding RNAs—not only shapes EMT heterogeneity but also drives adaptive evolution under therapeutic pressure (Tan et al., 2022). Whole-genome methylation analyses reveal increased hypermethylation at the CDH1 promoter in metastatic castration-resistant PCa (mCRPC), resulting in epithelial marker loss and ZEB1-mediated mesenchymal activation (Lee et al., 2020). Intriguingly, intermediate EMT (E/M) cells exhibit unique “bivalent domain” methylation patterns: partial methylation at epithelial gene promoters (FOXA1) and hypomethylation at mesenchymal loci (SNAI2), enabling rapid microenvironmental adaptation (Bhat et al., 2021; Liu Y. et al., 2023). Targeting DNMT3B reverses EMT phenotypes and restores drug sensitivity in enzalutamide-resistant cell lines (Wu et al., 2020). Histone modifications further regulate EMT transcription via chromatin remodeling (Yang et al., 2023). In AR inhibitor-resistant cells, H3K27ac enrichment at TWIST1 enhancers sustains mesenchymal traits (Chen et al., 2022), while dynamic H3K4me3 modifications at stemness-related genes (SOX2) couple EMT with cancer stem cell properties (Mitchell et al., 2023). Preclinical studies demonstrate that EZH2 inhibitors block this reprogramming, significantly improving paclitaxel response rates in PDX models (Yang et al., 2021). Non-coding RNAs amplify EMT heterogeneity through dual epigenetic-transcriptional control (Hashemi et al., 2022). For example, the long non-coding RNA MALAT1 recruits HDAC3 complexes to the CDH1 promoter, silencing its expression via histone deacetylation to promote invasion (Ferri et al., 2022). Clinically, epigenetic silencing of key EMT suppressors inversely correlates with enzalutamide resistance in CRPC patients, highlighting their potential as predictive biomarkers (Nikhil et al., 2020).
EMT and drug resistance in PCa
Overcoming therapy resistance represents one of the most critical challenges in oncology, as it is a leading cause of treatment failure in tumors (Vasan et al., 2019). Therapy resistance encompasses rejection of chemotherapy, radiotherapy, immunotherapy, and targeted therapies, along with both inherent and acquired resistance to conventional tumor treatments (Vasan et al., 2019). The management of locally advanced prostate tumors relies on androgen deprivation therapy (ADT); however, clinical outcomes remain limited. Following the initial response, these patients inevitably progress to CRPC (Falagario et al., 2023; Preisser et al., 2024), which is connected with various forms of epithelial plasticity, including EMT (Dunning et al., 2011; Teng et al., 2021). To support this hypothesis, early studies have indicated that stem cells associated with castration resistance in PCa may arise from cells that hcluding tumor-associated macrophages, tumor-associated fibroblasts, regulatory T cells, and myeloid-derived suppressor cells (Sun et al., 2012). These immunosuppressive cell populations have also been shown to promote EMT in tumor cells through the secretion of inflammatory cytokines or exosomes (Sun et al., 2012). This interplay has been validated in various solid tumors, including PCa. In PCa, the expression of N-cadherin is significantly linked to immunoregulatory features. N-cadherin-positive regions exhibit a local decrease in intraepithelial cytotoxic (CD8) T cells and an increase in immunosuppressive regulatory T cells (Miao et al., 2017). This correlation is associated with the expression of the IDO1 protein and its metabolite, kynurenine, in the predominantly N-cadherin-positive regions. In summary, the dynamic interactions between EMT and the TME play a critical role in tumor progression and immune evasion. Understanding these interactions can offer valuable insights into potential therapeutic targets for enhancing cancer treatment outcomes (Sun et al., 2012). EMT markers, including N-cadherin, have been reported to be upregulated following androgen deprivation therapy and can directly induce the transition of PCa to CRPC (Miao et al., 2017; Mickova et al., 2021). Similarly, transcription factors related to EMT have also been implicated in CRPC. For instance, several studies have indicated that the EMT transcription factor Snail is related to with elevated Gleason scores, and its ectopic expression has been shown to result in increased levels of AR and AR variants. Additionally, Skp2-mediated stabilization of Twist not only facilitates the progression of PCa to CRPC but also correlates with resistance to paclitaxel in PCa (Mickova et al., 2021; Ruan et al., 2017). Furthermore, TGF-β, a major regulator of EMT, has been implicated in the development of CRPC. When its upstream inhibitor FOXA1 is lost, TGF-β expression and activity are upregulated, further facilitating the progression of CRPC (Wang et al., 2023). Inhibitors of TGF-β receptors have been shown to enhance the sensitivity of advanced PCa to enzalutamide treatment (Paller et al., 2019).
Similarly, EMT significantly impacts the sensitivity of solid tumors, including PCa, to chemotherapeutic agents, including docetaxel, paclitaxel, and epirubicin (Dunning et al., 2011; Teng et al., 2021). These agents are often utilized as first-line treatments for CRPC or its lethal subtypes following ADT failure (Falagario et al., 2023; Preisser et al., 2024). Although these agents demonstrate effective therapeutic outcomes initially, PCa inevitably develops resistance to them over time, similar to ADT. While the specific molecular mechanisms remain unclear, it is widely acknowledged that EMT influences the sensitivity of PCa to these agents. Laboratory evidence supports this assertion; previous studies have demonstrated that cells resistant to chemotherapeutic agents undergo epithelial-to-mesenchymal transition, resulting in decreased levels of E-cadherin and upregulation of mesenchymal markers (Du and Shim, 2016). Inhibiting the EMT process or reintroducing E-cadherin can restore sensitivity to chemotherapeutic agents (Ni et al., 2013; Hanrahan et al., 2017). Additionally, transcription factors related to EMT, including ZEB1 and SKP2, have been implicated in chemotherapy resistance by promoting EMT in PCa cells. In conclusion, overcoming therapy resistance, particularly by targeting EMT and its regulatory pathways, is essential for enhancing the efficacy of treatments for PCa and other solid tumors (Preisser et al., 2024; Dunning et al., 2011).
EMT and cancer stem cell (CSC) phenotype and spatial heterogeneity in PCa
Cell plasticity is regarded as a hallmark of EMT, wherein tumor epithelial cells undergoing EMT may exhibit intermediate morphological, transcriptional, and epigenetic characteristics. These features encompass a spectrum of both epithelial and mesenchymal markers, referred to as quasi-mesenchymal intermediates, and are believed to be primary contributors to EMT-associated cell plasticity, which has been linked to tumor stemness (Lambert and Weinberg, 2021). This notion is supported by findings that prostate tumor cells exhibiting mesenchymal characteristics demonstrate enhanced invasiveness and stemness (Soundararajan et al., 2018; Navas et al., 2020). CSC hypothesis is an emerging model that elucidates various molecular features of malignant tumors, along with their propensity for recurrence, metastasis, and resistance to conventional therapies. CSCs have been isolated from tumors in PCa patients and are considered one of the primary contributors to tumor resistance and recurrence (Batlle and Clevers, 2017). Observations indicate that the expression levels of tumor stemness markers tend to rise with tumor progression, and it has been shown that PCa neuroendocrine cells (AR and PSA negative) may be associated with CSCs (Verma et al., 2023). Notably, growing evidence suggests that the activation of the EMT process in PCa cells is linked to the acquisition and maintenance of stem cell properties within PCa epithelial cells (Soundararajan et al., 2018). N-cadherin has been demonstrated to elevate the expression of prostate cancer stem cell markers (c-Myc, Klf4, Sox2, and Oct4) through the ErbB signaling pathway, thereby enhancing the formation of prostate tumorospheres. The upregulation of cancer stem cell markers is linked to PCa cells displaying more pronounced mesenchymal traits. Similarly, in contrast to the CD44-negative population, mesenchymal markers, including N-cadherin and vimentin, are highly upregulated in the CD44-positive population. Prostate tumor cells exhibiting mesenchymal characteristics tend to demonstrate enhanced invasiveness and stemness (Wang et al., 2016). In summary, the interplay between EMT and CSCs underpins the plasticity of tumor cells, contributing to their aggressive behavior and resistance to therapies. Understanding these mechanisms is crucial for developing strategies to target these adaptive processes and enhance treatment outcomes for PCa (Fontana et al., 2019). Concurrently, endothelial cell-derived IL-8 activates the AKT/mTOR pathway via CXCR receptors, promoting the shift of hybrid epithelial-mesenchymal (E/M) cells toward mesenchymal phenotypes (Lu et al., 2025). Furthermore, glutamine deprivation in the tumor core activates GCN2 kinase, which phosphorylates eIF2α to suppress epithelial gene translation, driving mesenchymal transition (Lu et al., 2024). In EMT-active regions, M2 macrophages and regulatory T cells are significantly enriched compared to normal areas, fostering an immunosuppressive niche (Han et al., 2023). These cells secrete IL-10 and TGF-β to induce EMT in neighboring epithelial cells and shield mesenchymal-like cells from CD8+ T cell-mediated cytotoxicity (Denk et al., 2025). Hypoxic, TP53-mutated EMT clones in the tumor core rely on HIF-1α (Guan et al., 2021), while AR-V7-positive clones at the invasive front dominate via WNT signaling activation (Tsao et al., 2021). Such spatial heterogeneity in EMT dynamics, governed by multi-layered regulatory networks, may offer novel therapeutic strategies to overcome treatment resistance in Pca.
EMT and the immunosuppressive microenvironment in PCa
The tumor microenvironment (TME) consists of various cell types, including cancer cells, infiltrating immune cells, and stromal cells, such as fibroblasts. Interactions among these different cell types can influence one another, thereby inducing changes in the TME that affect tumor progression and metastasis (Pitt et al., 2016; Aggarwal et al., 2021). Interestingly, there is an interaction between EMT and TME, two fundamental biological processes, and EMT is associated with the recruitment of immunosuppressive cell populations (tumor-associated macrophages, tumor-associated fibroblasts, regulatory T cells, and myeloid-derived suppressor cells) in TME (Aggarwal et al., 2021), and these immunosuppressive cell populations have also been reported to promote EMT in tumor cells by secreting cytokines or exosomes (Aggarwal et al., 2021), which has been demonstrated in a variety of solid tumors, including PCa, In PCa, N-cadherin expression is significantly associated with immunomodulatory profiles, with N-cadherin-positive regions exhibiting a local decrease in intraepithelial cytotoxic (CD8) T cells and an increase in immunosuppressive regulatory T cells (Sun et al., 2021), which is connected with the expression of IDO1 protein and its metabolite kynurenine in predominantly N-cadherin-positive regions (Sun et al., 2021).
Clinical correlation between EMT and prostate cancer
Recent advances in targeting EMT transcription factors have yielded promising clinical validation of Twist1 and Snail inhibitors in metastatic castration-resistant prostate cancer (mCRPC) (Taki et al., 2021). Studies demonstrate that combining Harmine derivatives with enzalutamide reduces Twist1 mRNA levels in mCRPC patients, correlating with prolonged radiographic progression-free survival (rPFS) (Dellal et al., 2020; Agarwal et al., 2023). However, while the STAT3/Snail dual-pathway inhibitor Napabucasin upregulates E-cadherin in treated tissues (Li et al., 2024), its use is limited by increased diarrhea incidence (Wang S. T. et al., 2024). The histone deacetylase inhibitor Vorinostat, combined with abiraterone, significantly extends overall survival in mCRPC patients with high EMT scores (Tanabe et al., 2024). This heterogeneity aligns with genome-wide methylation analyses, where ZEB1 and VIM demethylation strongly associates with PSA decline (Rajamäki et al., 2021; Davies et al., 2023). Interim analyses of TGF-β inhibitor/PD-1 antibody combinations in high-EMT mCRPC reveal rising objective response rates, with reduced EMT scores linked to enhanced intratumoral CD8+ T cell infiltration (Lin et al., 2021).
Pathways associated with EMT activation in PCa cells
Transforming growth factor beta (TGF-β)
TGF-β is a multifunctional cytokine synthesized by various tissue cells (Massagué and Sheppard, 2023). The TGF-β signaling pathway encompasses various multifunctional cytokines, their corresponding receptors, and intracellular signal transduction molecules, and is associated with several cellular activities, including EMT, growth arrest, and tissue fibrosis (Massagué and Sheppard, 2023). It has been established as a primary regulatory factor for EMT activation in PCa (Mirzaei et al., 2022). TGF-β promotes EMT activation in PCa by inducing vimentin and fibronectin while inhibiting E-cadherin levels, which is associated with the upregulation of EMT transcription factors following activation of the classical TGF-β signaling pathway (Smad-dependent pathway) (Mirzaei et al., 2022). The expression level of this protein is typically correlated with poorer prognosis and higher expression levels in PCa specimens (Torrealba et al., 2020). Conversely, negative regulators of TGF-β have been reported to exhibit decreased expression levels with the progression of PCa. For instance, FOXA1 (a negative regulator of neuroendocrine differentiation) displays lower expression levels in CRPC patients, which is linked to active TGF-β-induced cellular events, including EMT, suggesting potential activation of the EMT process in CRPC (Song et al., 2019). Similarly, another critical regulator of TGF-β effects is SOX5, which initiates EMT by binding to the TWIST1 promoter. A reduction in the expression level of this molecule results in the loss of the mesenchymal phenotype and migratory capacity of PCa cells (Hu et al., 2018). Furthermore, TGF-β has been shown to promote EMT activation in PCa through additional oncogenic pathways. For instance, TGF-β can initiate the EMT process in PCa by activating the PI3K/Akt signaling pathway, which dissociates the E-cadherin/catenin complex from the actin cytoskeleton (Torrealba et al., 2020; Song et al., 2019; Hu et al., 2018). In summary, TGF-β plays a crucial role in EMT activation in PCa through various pathways, including the Smad-dependent pathway and other oncogenic signaling pathways such as PI3K/Akt (Mirzaei et al., 2022; Torrealba et al., 2020; Song et al., 2019; Hu et al., 2018; Hamidi et al., 2017). Understanding these mechanisms is essential for developing therapeutic strategies aimed at targeting EMT and enhancing treatment outcomes for PCa.
AR signaling pathway and ADT therapy
PCa is primarily an androgen-dependent disease. The standard therapy for metastatic PCa involves inhibiting androgen synthesis, lowering circulating androgen levels, and blocking the AR (Falagario et al., 2023; Preisser et al., 2024). Previous literature has reported several clinical trial outcomes for second-generation ADT drugs. These drugs target the AR ligand-binding domain and, although they initially achieve significant therapeutic effects, they inevitably lead to resistance over time (Preisser et al., 2024; Dunning et al., 2011). This resistance is linked to changes in AR expression, the emergence of variant receptors, and specific mutations (Zheng et al., 2022). Notably, the relationship between the AR signaling pathway and EMT is intricate and not fully understood. Previous studies have indicated that AR can induce the expression of various proteases, including MMP2/9, and promote cellular invasion, which is linked to EMT activation (Li et al., 2007). Consequently, early research suggested that ADT might inhibit EMT in PCa. However, practical studies reveal a more complex relationship. ADT has been shown to induce EMT genes, with PCa cells exhibiting upregulated EMT-related genes and mesenchymal phenotypes following ADT treatment (Chen et al., 2017). AR-negative PCa cell lines (PC3 and DU145) demonstrate higher mesenchymal gene expression and reduced epithelial characteristics compared to androgen-dependent PCa cell lines (LNCaP) (Moll et al., 2022). This phenomenon may be attributed to ADT treatment diminishing AR’s inhibition of Sail genes, thereby promoting PCa EMT (Moll et al., 2022; Cmero et al., 2021). However, some studies indicate that EMT induction during ADT treatment may result from the upregulation of the chemokine CCL2 (Lee et al., 2018). CCL2 is known to enhance cell motility and is recognized as a paracrine regulator that promotes tumor metastasis (sai et al., 2018). Its expression is elevated during ADT treatment. Moreover, the emergence of AR variants following ADT treatment can influence EMT gene expression. For instance, AR-V7 has been demonstrated to induce mesenchymal genes and tumor stemness, fostering metastasis (Lee et al., 2018). Furthermore, emerging research highlights that estrogen receptor (ER) signaling drives disease progression following AR deprivation, with compensatory ER pathway activation playing a critical role. Specifically, the ERα subtype promotes tumor proliferation and bone metastasis via MAPK/ERK activation, correlating with reduced overall survival (Erdmann et al., 2022). In contrast, ERβ suppresses tumorigenesis by inhibiting NF-κB signaling (Yang J. et al., 2020). AR inhibition disrupts the ERα/ERβ balance, reshaping tumor biology (Wang et al., 2021). Post-AR suppression, ERα upregulation drives proliferation and induces EMT through MAPK/ERK activation (Chakraborty et al., 2023). While ERβ overexpression inhibits localized PCa growth in animal models, this protective effect diminishes after AR inhibition (Wang et al., 2022). Compensatory ER signaling triggered by AR-targeted therapies remodels tumor evolution and microenvironment adaptation via ERα/ERβ imbalance (Liu Q. et al., 2023). In summary, androgen deprivation therapy intricately links ER signaling to EMT in PCa. However, modulating AR or ER to control EMT remains a key challenge in advancing therapeutic strategies.
Inflammation and cytokines
EMT can also be induced by specific inflammatory factors and cytokines (Wang P. et al., 2024). IL-6, a cytokine belonging to the chemokine family, has been found at elevated levels in metastatic specimens from PCa patients and is associated with a mesenchymal phenotype in PCa (Wang P. et al., 2024; Nguyen et al., 2014). This indicates that IL-6 may act as an effective inducer of EMT in PCa. Moreover, TNF-α, a dimeric soluble cytokine, is regarded as a regulatory factor in EMT associated with PCa. Activation of the AKT/GSK-3β signaling pathway in PCa stabilizes Snail, a key mechanism driving EMT in tumor cells (Fontanella et al., 2021). Notably, the fibroblast growth factor (FGF) family has been linked to EMT in PCa. An in vitro study using PCa cell lines demonstrated that FGF2 enhances mesenchymal markers while reducing epithelial markers, thereby inducing EMT and promoting increased cellular invasion and metastasis (Wang et al., 2013). Mechanistically, this may result from FGF9 activating c-Jun-dependent TGF-β secretion in prostate stromal cells, which subsequently triggers EMT in prostate cancer cells through paracrine signaling (Wang et al., 2013; Huang et al., 2015; Jin et al., 2004). In summary, several cytokines and growth factors, including IL-6, TNF-α, and members of the FGF family, play crucial roles in the activation of EMT in PCa. Understanding the specific pathways and mechanisms by which these factors influence EMT could provide valuable insights for developing targeted therapies aimed at mitigating cancer progression and metastasis.
Treatment strategies related to EMT
Therapeutic strategies targeting EMT primarily focus on biomarkers capable of predicting disease outcomes. Recent studies have employed metrics such as hazard ratios (HRs) and receiver operating characteristic (ROC) curves to quantify the clinical predictive value of EMT biomarkers, though findings vary significantly across studies (Mazumder et al., 2022). Retrospective analyses using Cox proportional hazards models confirm that expression levels of core EMT transcription factors (Twist, Snail) and adhesion molecules (E-cadherin, N-cadherin) correlate strongly with patient survival outcomes (Qu et al., 2021). For instance, Twist overexpression associates with reduced progression-free survival (Shen et al., 2022), while Snail positivity increases mortality risk in colorectal cancer (Bao et al., 2022). Notably, prognostic implications differ by cancer type: Vimentin predicts poor outcomes in lung cancer (Bronte et al., 2021) but exhibits protective effects in PCa (Choudhry et al., 2023). ROC analyses further demonstrate that biomarker combinations like the E-cadherin/Vimentin ratio show promising sensitivity and specificity for early metastasis detection (Lee et al., 2020).
In PCa, epithelial plasticity is directly linked to poor clinical prognosis (Lee et al., 2020). Genomic analyses have identified distinct genetic signatures linked to various intermediate states of EMT, aiding in the identification of EMT-related transcription factors that can serve as biomarkers. For instance, a study by Jedroszka and colleagues classified patients into several groups based on their expression levels of AR, ESR1, and ESR2 (Zhang et al., 2014; Jędroszka et al., 2017). After analyzing 43 genes involved in EMT, they found that variations in gene expression could predict more aggressive phenotypes in individuals under 50 years old (Jędroszka et al., 2017). Similarly, CTCs exhibiting an EMT phenotype can predict disease recurrence and metastasis (Liu et al., 2020). Furthermore, prior studies have reported a risk scoring model derived from EMT-related genes to predict disease outcomes, demonstrating significant clinical benefits (Feng et al., 2022). Similar risk scoring models have also been reported in other tumors (He et al., 2023; Yang C. et al., 2020; Zhang Z. J. et al., 2023). These findings suggest that future research may specifically target patients with high expression of mesenchymal markers, exploring personalized immunotherapy for molecular subtypes exhibiting varying levels of EMT gene expression. As previously mentioned, in PCa, EMT appears to be a key mediator of acquired resistance to androgen deprivation and docetaxel therapies. EMT activation following ADT treatment is linked to castration resistance. Targeting or reversing the EMT process in epithelial cancer cells undergoing ADT treatment could be a promising strategy for enhancing PCa outcomes. Metformin, a widely used antidiabetic medication, has demonstrated effective antitumor activity (Yu and Suissa, 2023). Prior studies have indicated that it can reverse resistance to enzalutamide by targeting two key pathways closely associated with EMT regulation (TGF-β and STAT3), highlighting the feasibility of combining EMT inhibitors with ADT therapy (Liu et al., 2017). This is supported by several additional studies, including those demonstrating that cabazitaxel and TGF-β receptor inhibitors enhance sensitivity to enzalutamide and reverse the EMT process when combined with ADT treatment (Paller et al., 2019; Song et al., 2019). EMT activation impairs DNA repair capacity, increasing tumor mutational burden (Moyret-Lalle et al., 2022). In PCa metastases, EMT-high cells harbor more nonsynonymous mutations than epithelial counterparts, with enrichment in PI3K/AKT and WNT pathways driving clonal evolution (Therachiyil et al., 2022). Abiraterone treatment significantly expands EMT-driven AR-V7 splice variant-positive clones, revealing co-evolution between EMT and castration resistance (Gurioli et al., 2022). EMT reversibility enables phenotypic switching under therapeutic pressure (Shu et al., 2020). Animal models show transient increases in Vimentin+ cells within docetaxel-treated PCa bone metastases, which revert to baseline post-treatment, correlating with drug concentration gradients (Wei et al., 2024). Notably, EMT plasticity activates SOX2/OCT4 pathways to confer cancer stem cell-like properties, enhancing residual cell regeneration and drug tolerance (Marques-Magalhães et al., 2025). Clinically, patients with fluctuating EMT scores exhibit elevated recurrence risk (Kim et al., 2025). By remodeling the extracellular matrix (ECM) and fostering immunosuppressive microenvironments, EMT creates niches that favor resistant clone expansion (Wang Y. et al., 2024). Moreover, the selective estrogen receptor modulator raloxifene has been identified as a potential treatment for PCa. In vivo studies have demonstrated that this drug inhibits EMT by suppressing N-cadherin, SLUG, SNAIL, vimentin, and matrix metalloproteinases, thereby impacting the efficacy of ADT treatment (Di Zazzo et al., 2019).
Recent breakthroughs in detecting circulating tumor cells (CTCs) exhibiting EMT features have significantly improved prognostic accuracy in PCa. These advancements leverage multimodal capture strategies and molecular profiling to enhance detection reliability (Cai et al., 2024). Traditional CTC detection relies on epithelial markers like EpCAM. However, EMT-induced loss of these markers often leads to undetected mesenchymal CTCs, limiting diagnostic sensitivity (Di Zazzo et al., 2019). Emerging technologies address this limitation by integrating physical properties, functional biomarkers, and single-cell analysis, enabling precise capture and molecular characterization of EMT-heterogeneous CTCs (Guan et al., 2024). For example, the “Tri-Modal Chip” combines EpCAM antibody coatings, size-based filtration, and deformability analysis. This method improves CTC detection rates in mCRPC and distinguishes epithelial, hybrid, and mesenchymal CTC subtypes (Li et al., 2025). Studies indicate that patients with higher proportions of mesenchymal CTCs (M-CTCs) experience shorter progression-free survival (PFS) (Du et al., 2024). The aggressive behavior of mesenchymal CTCs correlates with their metabolic activity. New platforms now evaluate metabolic states using JC-1 mitochondrial membrane potential staining and lactate secretion measurements (Guder et al., 2024). Notably, CTCs with elevated lactate secretion strongly associate with bone metastasis risk in PCa, outperforming PSA levels as a predictive biomarker (Bergmann et al., 2025). Furthermore, real-time monitoring of CTC glycolytic activity via extracellular acidification rate (ECAR) analysis provides functional evidence for dynamic EMT progression (Luan et al., 2024).
In summary, these findings indicate that targeting the EMT process in PCa may represent an effective therapeutic strategy. However, a comprehensive understanding of the molecular biology of EMT and its relationship with established molecular subtypes of advanced PCa is essential for effectively implementing EMT-targeted therapeutic strategies in clinical trials.
Conclusion and future directions
The era of personalized precision medicine has begun in oncology, yet enhancing patient survival and improving prognosis continue to pose significant challenges. Research on EMT highlights the importance of understanding the interplay between cellular plasticity, stemness, and treatment response. These processes are closely associated with tumorigenesis, invasiveness, migration, metastasis, and interactions with TME. EMT can be induced by various drivers and effectors, which may serve as prognostic biomarkers or targets for interventions in metastatic disease. Furthermore, the role of EMT in cancer progression and therapeutic resistance has been extensively investigated. In PCa, EMT is upregulated after ADT and is correlated with the emergence of CRPC. This implies that future translational research on the “reprogramming” of cancer cell fate through EMT could empower lethal PCa to overcome treatment resistance and improve patient survival. Unfortunately, there are currently few therapeutic agents or methods capable of effectively modulating the EMT process to enhance the efficacy of cancer treatments. In cellular and animal studies, targeting specific transcriptional genes has been shown to reverse EMT and enhance tumor treatment sensitivity. However, achieving long-term success in humans remains fraught with considerable risks and challenges.
Author contributions
XW: Writing – original draft, Writing – review and editing. RL: Writing – original draft, Writing – review and editing. WL: Writing – original draft, Writing – review and editing. QY: Writing – original draft, Writing – review and editing. QnY: Writing – original draft, Writing – review and editing. TL: Conceptualization, Writing – original draft, Writing – review and editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This manuscript was funded by National Nature Science Foundation of China (No. 82360295 and 82060276), the Doctor Start-up Fund of Affiliated Hospital of Guizhou Medical University (gyfybsky-2023-03), the Science and Technology Department of Guizhou Province (QianKeHeJiChu-ZK[2021]YiBan382), and the Science and Technology Foundation Project of Guizhou Provincial Health Commission (gzwkj2024-150).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: prostate cancer, epithelial-mesenchymal transition, tumor progression, tumor drug resistance, heterogeneity
Citation: Wei X, Liu R, Li W, Yu Q, Yang QT and Li T (2025) Advances in research regarding epithelial-mesenchymal transition and prostate cancer. Front. Cell Dev. Biol. 13:1583255. doi: 10.3389/fcell.2025.1583255
Received: 25 February 2025; Accepted: 09 May 2025;
Published: 30 May 2025.
Edited by:
Luis Diambra, National University of La Plata, ArgentinaReviewed by:
Magdalena Julita Orzechowska, Medical University of Lodz, PolandAlexander Zaslavsky, University of Michigan, United States
Copyright © 2025 Wei, Liu, Li, Yu, Yang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Tao Li, MjAyNDAyMDAyMDE0OUBzdHUuZ21jLmVkdS5jbg==
†These authors have contributed equally to this work