Patients with epithelial ovarian cancer (EOC) are often diagnosed with peritoneal metastasis and ascites, the accumulation of intraperitoneal fluid containing nonmalignant cells. However, the interactions between EOC and nonmalignant cells before peritoneal metastasis remain unclear. To investigate this, whole EOC spheroids were observed using a multiphoton microscope, and their invasion ability was assessed. Mesothelial cells were identified as notable components of ascites through morphological assessment, immunohistochemical/immunofluorescence staining, and single-cell RNA sequencing analyses. Almost all EOC cells were spheroids, with 60% containing mesothelial cells. EOC cells quickly generate aggregated spheroids with mesothelial cells, and these aggregated cancer-mesothelial spheroids (ACMSs) invade collagen or mesothelial layers. Mesothelial cells forming ACMSs initiated the invasion. RNA sequencing analysis revealed marked RNA expression changes in mesothelial cells, whereas the changes in EOC cells were minor. Transforming growth factor-β1-stimulated mesothelial cells showed increased invadopodium formation along with fascin-1 up-regulation. These findings suggest that EOC cells alter mesothelial cells through ACMSs, thereby elucidating the rapid spread of EOC in the abdominal cavity.

Fascin, an actin-bundling protein universally upregulated in metastatic tumors, drives tumor migration and invasion by promoting filopodia and invadopodia formation, establishing it as a pivotal therapeutic target. Herein, copper-paeonol nanozymes (CuPaeNs) is engineered through metal-phenolic complexation, mimicking natural enzyme metal-coordination microenvironments to confer peroxidase-like activity. This enzymatic capability drives the conversion of tumor-associated H2O2 into cytotoxic hydroxyl radicals, inducing oxidative damage in malignant cells. Notably, beyond inducing tumor catalytic therapy via targeted ROS generation, CuPaeNs directly disrupted the actin-bundling activity of fascin, as evidenced by molecular docking, isothermal titration calorimetry, co-immunoprecipitation, and immunofluorescence assays. Transcriptomic and biochemical analyses further revealed that CuPaeNs suppressed melanoma glycolysis by blocking the fascin-YAP1-PFKFB3 signaling axis. This study establishes metal-phenolic nanozymes as a dual-functional strategy that simultaneously triggers ROS overproduction to amplify tumor oxidative stress and disrupts fascin-mediated metastasis, thereby modulating tumor metabolic reprogramming. This coordinated intervention establishes a novel treatment framework for malignancies characterized by fascin overexpression.

ABSTRACT The incidence of prostate cancer in middle‐aged and elderly men is increasing year by year, and the existing drug treatment programs have limitations. In this study, a pH‐responsive micelle loaded with doxorubicin (DSPE‐PEG‐pronethalol‐DOX micelle nanoparticles, DOX@DSPE‐PEG_Prone) was prepared for the treatment of prostate cancer. The micelles were synthesized by esterification of SRY‐Box transcription factor 2 (SOX2) inhibitor pronethalol and DSPE‐PEG‐COOH, which could self‐assemble into micelles in water and encapsulate DOX. The characterization results show that DOX@DSPE‐PEG_Prone have good water solubility, stability, and drug loading, and exhibit charge reversal and rapid drug release characteristics in the tumor microenvironment. In vitro experiments showed that DOX@DSPE‐PEG_Prone could enhance the efficacy of DOX and effectively inhibit the proliferation and migration of prostate cancer cells. DOX@DSPE‐PEG_Prone successfully down‐regulated the expression of SOX2 in prostate cancer cells and inhibited the formation of invadopodia in prostate cancer cells. In vivo experiments showed that DOX@DSPE‐PEG_Prone could significantly inhibit the growth of subcutaneous tumors of prostate cancer without obvious organ toxicity. Overall, this study provides a potential drug delivery system for the treatment of prostate cancer.

Translational reprogramming enables cancer cells to drive tumour progression and metastasis. eIF3i is a core component of the translational regulatory machinery, but the underlying mechanisms through which it promotes tumour metastasis remain unclear. Proteomic analysis identified eIF3i-regulated targets. Functional validation utilised in vitro and in vivo models, including migration/invasion assays, polysome profiling, RNA-binding assays (RIP and RNA pull-down), and mouse metastatic models. Clinical relevance was assessed in CRC patients with liver metastases. eIF3i was significantly overexpressed in metastatic CRC. Its knockdown inhibited cell migration, invasion, epithelial-mesenchymal transition (EMT), invadopodia formation in vitro, and lung metastasis in vivo. NELFCD was identified as a key downstream target, whose translation is directly promoted by eIF3i binding to its mRNA, independent of transcription. NELFCD knockdown phenocopied the anti-metastatic effects of eIF3i depletion. Crucially, the pro-metastatic capacity of eIF3i overexpression was abolished by concurrent NELFCD knockdown. eIF3i and NELFCD protein levels showed a significant positive correlation in clinical CRC metastases. The eIF3i-NELFCD axis drives CRC metastasis by directly upregulating NELFCD translation, thereby facilitating EMT and invadopodia formation. This pathway represents a promising therapeutic target for inhibiting metastatic progression in CRC.

p190A has been studied across various cancer types, and mutation rates of up to 20% were observed in some cancers, supporting the significance of p190A in carcinogenesis. Since the relevance of p190A in bladder cancer has not been addressed so far, we attempted to explore it. Evaluation of TCGA high-throughput sequencing datasets revealed p190A mutations in up to 8% of bladder cancer samples across several studies. Employing immunohistochemistry on tissue microarray that included 202 BC patient samples, we observed that lower p190A expression correlates with increased invasiveness and poorer survival outcomes. These findings suggested that p190A may have a tumor suppressor function in bladder tissue, consistent with its anticipated function in ploidy-control. p190A knockdown resulted in chromosomal instability in ureter-derived epithelial cells with otherwise normal karyotype, supporting its potential involvement in tumorigenesis. Loss-of-function studies in low-invasive bladder RT4 cell line and gain-of-function experiments in two highly invasive bladder cancer cell lines (T24 and BFTC) demonstrated that p190A influences cell migration and invasion in vitro, as determined by scratch assay and Boyden chamber approaches. This conclusion was further validated by ex vivo porcine bladder invasion approach, invadopodia formation, and gelatin degradation assays. Pathway analysis revealed that altered p190A expression influences both the Rho-ROCK-dependent LIMK1-cofilin pathway and the phosphorylation of cortactin by focal adhesion kinase, both of which regulate critical cellular processes such as actin network organization and polarization to facilitate efficient, coordinated cell migration and division. In summary, our results indicate that p190A has a genuine role in controlling cell-ploidy and regulates actin dynamics in the bladder urothelium, while loss of p190A results in genome instability and drives bladder cancer initiation and progression through deregulated actin dynamics.

TGF-β induces a decrease in CAPZA1 expression to promote the invasiveness of hepatocellular carcinoma cells.

Synthesisof 3-aminowithaferin A and its imine congeners to identify promising lead molecules for future development as anti-cancer agents. 3-Aminowithaferin A was synthesized through aza-Michael addition using liquid ammonia as a nucleophile. In order to obtain imine congeners various aldehydes were allowed to undergo addition-elimination with 3-aminowithaferin A. All the newly synthesized compounds were screened for their cytotoxicity against eight cancers and one normal cell line using MTT assay. One of the imine analogs, referred to as compound 13, exhibited significant antiproliferative and anti-metastatic properties across various cell lines, particularly in triple-negative breast cancer lines, with an IC50 value ranging from 507 nM to 2.475 µM. Compound 13 effectively inhibited the formation of invadopodia and filopodia, underscoring its anti-invasive properties. Additionally, immunoblotting studies demonstrated a consistent decrease in the expression of various epithelial-to-mesenchymal transition (EMT) markers in the presence of compound 13, further confirming its anti-metastatic properties.

BackgroundEndophilin A, a family of Bin-Amphoterisin-Rvs (BAR) domain-conserved proteins, is found in several tissues and is associated with disease pathogenesis. In patients with breast cancer, endophilin A expression pertains to boosted tumour cell endocytosis, migration, and invadopodia formation, potentially linked to a poor prognosis.MethodsThis study aimed to determine the expression of endophilin A isoforms (SH3GL1, SH3GL2, and SH3GL3) in breast cancer using databases like UALCAN, GEPIA2, TIMER 2.0, geneMANIA, Enrichr, Km Plotter, and GENT2.ResultsWe report the elevated expression of SH3GL1 in TNBC and HER2 subtypes of breast carcinoma, and that positively correlated with advancing stage as well as lymph node metastasis, compared to SH3GL2 and SH3GL3. Additionally, the study demonstrates that in contrast to SH3GL1 and SH3GL3, elevated SH3GL2 transcript levels were positively associated with improved Overall Survival (OS), Relapse Free Survival (RFS), and Distance Metastasis Free Survival (DMFS compared to low expression levels among the breast cancer patients. Further, we also show the associated immune filtration with each endophilin isoform and link the expression of endophilin A isoform with p53 expression.ConclusionsBased on our findings, it is possible to conclude that endophilin A isoforms—long recognised for orchestrating endocytosis and metastatic behaviour—may represent a critical molecular fulcrum in breast cancer progression. In particular, elevated expression of endophilin A2 (SH3GL1) and SH3GL2 strongly correlates with poor prognosis and node-positive breast cancer, highlighting their potential as promising biomarkers for breast cancer assessment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-03382-6.

BackgroundGastric cancer is the fifth most common malignancy and third leading cause of cancer death in China, with advanced-stage five-year survival below 20%. βIII-tubulin (TUBB3) is overexpressed in cancers but its role in gastric cancer remains unclear.MethodsTUBB3 expression was analyzed using TCGA data and clinical samples. Knockdown models assessed its effects on proliferation, migration, and invasion in vitro and in vivo.ResultsTUBB3 was significantly upregulated in gastric cancer tissues versus normal mucosa. High TUBB3 correlated with poorer disease-free and overall survival but not other clinicopathological features. Functionally, TUBB3 knockdown inhibited proliferation via G2/M arrest and reduced migration/invasion by disrupting invadopodia, without affecting apoptosis, EMT, or ECM degradation. In vivo, TUBB3 depletion suppressed tumor growth and metastasis. Mechanistically, TUBB3 promoted G2/M transition via p21/Cyclin B1 and enhanced invasiveness through Cortactin/JNK activation.ConclusionTUBB3 overexpression predicts poor prognosis in gastric cancer. It drives proliferation via cell cycle regulation and metastasis through invadopodia formation, suggesting its potential as a therapeutic target.

CRABP2 promotes peritoneal metastasis in CRC through TGF-β/Smad-mediated EMT signaling and invadopodia formation.

Brain metastases (BM) critically reduce breast cancer (BC) patients' survival. Extravasation is pivotal for BM development, but the underlying events at the blood-brain barrier (BBB) remain elusive. We aimed to unravel the players and mechanisms governing BC cells (BCCs)-BBB interaction. For that, mixed cultures of human brain microvascular endothelial cells (HBMECs), mimicking the BBB, and brain-tropic triple-negative BCCs (MDA-MB-231 Br4), or non-brain-tropic (MDA-MB-231) or non-metastatic cells (MCF-7) were established. Temporal and spatial analysis of BCCs-BBB interactions (live-cell imaging automated microscopy), and assessments of endothelial-to-mesenchymal transition (EndMT) markers, transcription factors, cytoskeletal proteins, and morphology (immunocytochemistry) were performed. BBB integrity (permeability, transendothelial electrical resistance) and endothelial migration (wound-healing) were also assessed. Our results revealed that contrasting with non-metastatic and non-brain-tropic cells, BCCs quickly developed an invasive, migratory phenotype, characterized by invadopodium formation and reduced roundness. Spatial analysis showed different positioning of BCCs relative to the BBB endothelium over time, with 14% of BCCs transmigrated after 3h, compromising BBB integrity through endothelial holes, reduced tightness, and increased permeability. Prior to transmigration, alterations in adhesion markers (E-selectin, ICAM-1, CD24, CD34, β3-integrin, Sialyl-Lewis X) were observed. EndMT was also evident by decreased endothelial (β-catenin and pan cytokeratin) and increased mesenchymal (vimentin, neuronal-cadherin, Slug, ZEB1) markers, elongation (RhoA, α-SMA), nuclear deformation, and migratory capacity. Caveolin-1 silencing in HBMEC decreased BCCs transmigration. This study reveals significant BBB phenotypic and structural changes, facilitating both paracellular and transcellular BCCs transmigration. These findings provide advanced understanding of BCCs trafficking across the BBB, aiding strategy development to prevent extravasation and BM.

Bladder cancer (BCa) is one of the most common malignant tumors of the urinary system, but its pathogenesis is still unclear. T1G3 BCa is particularly invasive and relapses readily after treatment, with progression to invasive cancer or distant metastasis. Therefore, identification of the molecular mechanism by which it invades and metastasizes to guide treatment and predict patient prognosis is needed. Cofilin1 plays an important role in regulating gene expression and the invasiveness of tumors. In this study, we show that Cofilin1 is highly expressed in BCa and lymph nodes with metastasis, which is positively related to the grade of BCa, and is significantly related to clinicopathological parameters and cancer-specific survival. Phenotypic analysis reveals that Cofilin1 knockout inhibits the proliferation and migration of BCa cells, whereas Cofilin1 overexpression promotes the opposite phenotype. Cofilin1 binds to cortactin, thereby reducing the expression of F-actin and promoting the formation of invadopodia in BCa cells. Further experiments reveal that TCF7L2 can bind to the promoter of Cofilin1 and transactivate it, promoting a malignant phenotype. TCF7L2 may also reverse the inhibitory effect of miR-206 on the binding of Cofilin1 and cortactin and promote the metastasis of BCa by inhibiting the transcription maturation of miR-206. This study confirms that Cofilin1 is an oncogene in T1G3 BCa, and the TCF7L2/miR-206/Cofilin1 signaling pathway plays an important role in the formation of invadopodia in BCa.

BackgroundAvian reovirus (ARV) is an oncolytic virus that induces autophagy and apoptosis in cancer cells, modulates the immune response, and exposes tumor-associated antigens to the immune system, making it a promising candidate for cancer therapy. Cancer cell migration and invadopodia formation are essential processes in metastasis, and targeting these mechanisms could be beneficial in limiting cancer progression.MethodsThis study investigated the effects of ARV p17 protein on cancer cell migration and invadopodia formation in HeLa and A549 cell lines. Molecular assays were conducted to examine the expression and interactions of key signaling molecules, including nucleoporin Tpr, p53, PTEN, FAK, Src, Rab40b, PI3K, Akt, TKs5, and Nck1. Analysis of TKs5, Nck1, and Rab40b mRNA levels by quantitative real-time RT-PCR. Furthermore, invadopodia detection, gelatin degradation assay, and Fluorescence imaging was performed to visualize invadopodia structures and assess extracellular matrix degradation. Additionally, rescue experiments were performed by co-transfecting cells with mutant PTEN (C124A), TKs5, or Rab40b plasmids to confirm their roles in mediating the effects of p17.Resultsp17 suppressed nucleoporin Tpr, resulting in the activation of p53 and upregulation of PTEN. This blocked the formation of the FAK-Src complex and inhibited the Rab40b-PI3K-Akt signaling pathway. p17 also transcriptionally downregulated TKs5, Nck1, and Rab40b, thereby reducing the formation of TKs5-Nck1 and TKs5-Rab40b complexes, which are critical for invadopodia formation. Fluorescence imaging confirmed a marked reduction in invadopodia formation and matrix degradation in cells expressing p17. Restoration of invadopodia formation upon co-transfection with mutant PTEN, TKs5, or Rab40b confirmed that these molecules are key mediators of p17’s inhibitory effects.ConclusionARV p17 inhibits cancer cell migration and invadopodia formation by activating the p53-PTEN pathway and suppressing essential signaling and scaffolding complexes (FAK-Src, Rab40b-PI3K-Akt, TKs5-Nck1, and TKs5-Rab40b). These findings suggest that p17 plays a crucial anti-metastatic role and may serve as a novel therapeutic agent for targeting invasive cancer cells.

Integrins provide an essential bridge between cancer cells and the extracellular matrix, playing a central role in every stage of disease progression. Despite the recognized importance of integrin phosphorylation in several biological processes, the regulatory mechanisms and their relevance remained elusive. Here we engineer a fluorescence resonance energy transfer biosensor for integrin β1 phosphorylation, screening 96 protein tyrosine phosphatases and identifying Shp2 and PTP-PEST as negative regulators to address this gap. Mutation of the integrin NPxY(783/795) sites revealed the importance of integrin phosphorylation for efficient cancer cell invasion, further supported by inhibition of the identified integrin phosphorylation regulators Shp2 and Src kinase. Using proteomics approaches, we uncovered Cofilin as a component of the phosphorylated integrin-Dok1 complex and linked this axis to effective invadopodia formation, a process supporting breast cancer invasion. These data further implicate dynamic modulation of integrin β1 phosphorylation at NPxY sites at different stages of metastatic dissemination.

BackgroundOral cancer (OC) is one of the major types of cancer and the most common cause of cancer-related mortality in Asia. In recent years, matrix stiffness in the tumor microenvironment has been found to play an important role in regulating tumor cell behavior. However, the regulatory mechanisms associated with matrix stiffness in OC cells remain unclear.MethodsIn this study, polyacrylamide gels with different stiffness were prepared to simulate low versus high matrix stiffness environments in tumor tissues by adjusting the acrylamide and cross-linker concentrations. Subsequently, the effects of different stiffness on OC cell survival, migration, invasion and invadopodia formation were explored based on cell counting kit-8 (CCK-8), Transwell and confocal microscopy. Meanwhile, the levels of markers relevant to phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), apoptosis (BAX and BCL2) as well as metastasis (Cadherin-1, CDH1; Cadherin-2, and CDH2) were calculated via western blotting and real-time quantitative PCR.ResultsAccording to the results, high matrix stiffness was seen to contribute to the increased number of migrated and invaded cells as well as the enhanced viability of OC cells, along with the aggravated invadopodia formation and the up-regulation in CDH2 and BCL2 levels yet the down-regulation in CDH1 and BAX levels. Elevated PI3K/AKT phosphorylation levels were also seen in high matrix stiffness-mediated OC cells, and the intervention using LY294002 could visibly overturned the effects of high matrix stiffness on the cell migration, invasion and invadopodia formation of OC cells.ConclusionsThis study reveals that matrix stiffness may enhance the invasiveness and anti-apoptotic ability of OC cells by activating the PI3K/AKT pathway, which provides a new idea for exploring the microenvironmental regulation of tumor mechanics and targeted intervention strategies.

The appearance of hybrid epithelial-mesenchymal (E/M) cells expressing E-cadherin is favourable for the establishment of pro-invasive function. Although the potential role of E-cadherin in cancer invasion is now accepted, the molecular mechanisms involved in this process are not completely elucidated. To gain further insight, we focused our analysis on invadopodia formation, an early event in the invasion process. We used models of E/M hybrid cell lines, tissue sections and patient-derived xenografts from a multi-centre clinical trial. E-cadherin involvement in invadopodia formation was assessed using a gelatin-FITC degradation assay. Mechanistic studies were performed by using proteomic analysis, siRNA strategy and proximity ligation assay. We showed that E-cadherin is a critical component of invadopodia. This unexpected localization results from a synergistic trafficking of E-cadherin and MT1-MMP through a Rab vesicle-dependent pathway. Modulation of E-cadherin expression or activation impacted invadopodia formation. Moreover, colocalization of E-cadherin and Actin in "ring structures" as precursors of invadopodia reveals that E-cadherin is required for invadopodia structuration. E-cadherin, initially localised in the adherens junctions, could be recycled to nascent invadopodia where it will interact with several components enriched in invadopodia, such as Arp2/3, Cortactin or MT1-MMP. The trans-adhesive properties of E-cadherin are therefore essential for structuring invadopodia. This new localisation of E-cadherin and its unexpected role in cell invasion shine a new light on hybrid E/M transition features in tumoral invasion.

Abstract Purpose: Many molecular mechanisms underlying tumor escape, in which cancer cells undergo EMT and thereby acquire metastatic potential and cancer stemness, have been elucidated, and these efforts have led to the development of various novel drugs. However, many patients do not necessarily benefit from the treatments. This may be because cancer cells diversify and evolve through intrinsic changes that occur within the cancer cells themselves via EMT, and extrinsic changes that are modified by the host environment, in an attempt to escape the attacks of therapeutics and immune surveillance. Considering this situation, further in-depth research is needed to achieve complete cure in more patients. In this study, we focused on the changes in gene expression that occur in cancer cells after achieving EMT, and attempted to elucidate the evolutionary mechanisms that further promote tumor escape leading to robust treatment resistance. Results: We comprehensively analyzed gene expression in mouse melanoma B16-F10 cells stably expressing Snail, a key EMT-governing transcription factor, by GeneChip microarray, and found that IL10RB expression was strikingly increased as compared to that of mock control. Transfection with siRNA-snail into the cells abrogated both Snail and IL10RB expression, suggesting that this is regulated by Snail. Transfection with siRNA-il10rb significantly reduced cell invasion, adhesion, and chemoresistance as compared to transfection with control siRNA, suggesting a key functional role of IL10RB in tumor malignancy. Il10rb gene transduction into mouse IL10RB(low) cell lines (NHOS and Colon26) significantly enhanced cell invasion, adhesion, and chemoresistance, accompanied by dramatic morphological changes - formation of numerous tentacles/invadopodia. RNA-sequencing analysis of the IL10RB transfectants revealed that gene expression of actin and related genes, which are required for invadopodia formation and drug resistance, and of enzymes, which are required for invasion and metastasis, was markedly increased than that in mock control. In the in vivo settings, IL10RB+ tumor growth and metastasis were extremely slower after implantation in mice than those of mock control. However, T cells and NK cells were dramatically decreased in the spleens of the IL10RB+ tumor-implanted mice, and their cytotoxic activity was also significantly reduced, suggesting induction of immune suppression and dysfunction. Surprisingly, chemotherapy significantly exacerbated both IL10RB+ tumor growth and metastasis in the mice, while immunotherapy with anti-IL10RB blocking mAb significantly induced anti-tumor effects without such adverse events. Conclusions: These results suggest that IL10RB is a key molecule that regulates tumor escape and intractability post Snail-induced EMT. Targeting IL10RB may be a promising strategy for improving clinical outcomes in cancer therapy. Citation Format: Chie Kudo-Saito, Hiroki Ozawa, Hiroshi Imazeki. IL10RB is a key molecule that regulates tumor escape through invadopodium formation and immune dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2632.

This study aimed to assess the expression of invadopodia-related proteins in mucoepidermoid carcinoma and their influence on this tumor's invasiveness. Twenty-seven mucoepidermoid carcinoma grading samples were evaluated for the expression of Tks4, Tks5, cortactin, and MT1-MMP and compared to 10 control samples of normal-looking salivary glands by immunohistochemistry. For invitro analysis, immunofluorescence identified the expression of invadopodia-related proteins in the mucoepidermoid carcinoma cell line. Invadopodia formation and invasion assays were performed after silencing of Tks4 and Tks5 to evaluate invasiveness. The invadopodia-related proteins were expressed significantly higher in mucoepidermoid carcinoma samples when compared to the control group. Positive expression of these proteins was identified in the mucoepidermoid carcinoma cell line. Knockdown of Tks4 and Tks5 reduced both gelatin degradation and invadopodia activity in mucoepidermoid carcinoma cell lines. Our results suggest that mucoepidermoid carcinoma behavior can be mediated by the expression of invadopodia-related proteins. Tks4 and Tks5 play a role in the invasiveness of mucoepidermoid carcinoma, mediated by invadopodia.

The aim of this study was to verify whether the expression of proteins related to the formation of invadopodia, MT1-MMP, cortactin, Tks-4 and Tks-5 is associated with the degree of tumor invasiveness of different types of unicystic ameloblastomas. An immunohistochemical study was performed on 29 unicystic ameloblastoma (UA) samples, 9 conventional ameloblastoma (CAM) samples and 9 dental follicle (DF) samples. The potential for tumor invasiveness was assessed based on the immunoexpression of the following invadopodia-forming proteins: MT1-MMP, cortactin, Tks-4 and Tks5. Mural unicystic ameloblastoma (MUA) showed higher MT1-MMP, cortactin, Tks-4, and Tks-5 immunoexpression than luminal and intra-luminal types. Conventional ameloblastoma exhibited lower MT1-MMP, cortactin, and Tks-5 expression compared to MUA. MUA's cystic capsule neoplastic cells had significantly higher MT1-MMP, cortactin, Tks-4, and Tks-5 expression than lumen cells. Dental follicles showed minimal expression. Neoplastic cells in the cystic capsule of mural unicystic ameloblastomas showed higher invadopodia-related protein expression than lumen and luminal/intraluminal cells, suggesting that proximity to the bone region influences the aggressive behavior of mural unicystic ameloblastomas more compared to other subtypes.

Cofilin is a pivotal actin-binding protein that plays a central role in regulating cytoskeletal dynamics, contributing to essential cellular processes such as migration, invasion, intracellular trafficking, and apoptosis. Dysregulation of cofilin is increasingly recognized to play a role in the pathogenesis and progression of various cancers, including gliomas and colorectal, breast, and bladder cancers. Cofilin facilitates cancer cell motility and metastasis by severing actin filaments, promoting invadopodia formation, and inducing epithelial-to-mesenchymal transition. Cofilin also modulates oncogenic signaling pathways, such as the phosphoinositide 3-kinase/protein kinase B and Rho guanosine triphosphatase pathways, and influences mitochondrial dynamics, thereby contributing to apoptosis resistance, metabolic reprogramming, and immune evasion. Recent advances in high-resolution imaging and multiomics analyses have revealed the spatiotemporal regulation of cofilin in the tumor microenvironment and its potential for use as a diagnostic and prognostic biomarker. Elevated cofilin expression is correlated with poor clinical outcomes and resistance to therapies, making cofilin an attractive target for cancer treatment. Preclinical models have demonstrated that targeting cofilin or its upstream regulators can improve therapeutic responses and suppress metastasis. This review explores the structural, functional, and regulatory roles of cofilin in cancer biology and highlights its emerging therapeutic potential. Future research should focus on the development of selective inhibitors and personalized treatment strategies to leverage cofilin as a target in precision oncology.