Search Results (2,501)

Background: The efficacy of chemotherapy in triple-negative breast cancer (TNBC) is limited by intrinsic resistance and the tumor microenvironment (TME). Accumulating evidence reveals a mechanistic connection between programmed death-ligand 1 (PD-L1) and c-x-c motif chemokine receptor 4 (CXCR4), which dominate stroma barriers, immune escape, and cancer metastasis. Earlier studies have shown that dual suppression of c-x-c motif ligand 12 (CXCL12)/CXCR4 and programmed cell death-1 (PD-1)/PD-L1 pathways regulates extracellular matrix (ECM) deposition, activation of cancer-associated fibroblasts (CAFs), and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. Methods: We combined BsNb PX4, a bispecific nanobody targeting PD-L1 and CXCR4, with paclitaxel or gemcitabine in multiple tumor cell lines and human peripheral blood mononuclear cell (hPBMC)-reconstituted xenograft mouse models. Antitumor activity was assessed by CCK-8, flow cytometry, and ELISA, and immune cell infiltration and TME remodeling were examined by immunofluorescence, immunohistochemistry, cytokine assays, and RNA-seq. Results: In MDA-MB-231 cells, BsNb PX4 synergistically enhanced paclitaxel-induced growth inhibition and apoptosis via G₂/M cycle arrest. This combinatorial strategy profoundly remodeled tumor immunity by expanding CD8⁺ T cells and depleting Foxp3⁺ CD4⁺ regulatory T cells (Tregs), while concurrently restoring T-cell cytotoxicity and skewing the cytokine balance toward an antitumor state, with elevated IFN-γ and reduced TGF-β1. Notably, compared with paclitaxel monotherapy, the combination significantly elevated intratumoral CD8⁺ T-cell infiltration, decreased Treg abundance, and exerted robust inhibitory effects on tumor growth and metastasis in humanized TNBC xenografts. Conclusions: These findings reveal that dual blockade of PD-L1 and CXCR4 acts synergistically with chemotherapy by triggering tumor cell apoptotic effects and reversing the immunosuppressive microenvironment, thereby emerging as a promising therapeutic strategy for TNBC. Full article

Metastasis-associated protein 1 (MTA1), an oncogenic transcriptional regulator, is overexpressed in canine urothelial carcinoma (UC) and is associated with aggressive clinicopathological features. However, its functional role and molecular mechanisms in canine UC remain poorly understood. Here, we investigated the contribution of MTA1 to epithelial-to-mesenchymal transition (EMT) and its interaction with BRAF signaling. MTA1 silencing in two canine UC cell lines significantly inhibited cell proliferation, cell survival, migration, and xenograft tumor growth. Mechanistically, MTA1 knockdown reduced the expression of MTA2, MTA3, and COX2, while producing unexpected changes in key EMT regulators, including Snail, Slug, and Cyclin D1, suggesting the activation of compensatory signaling pathways. MTA1 silencing also decreased mutant BRAF expression in AxA cells while increasing wild-type BRAF expression in SH cells, indicating context-dependent regulation of BRAF signaling. In AxA cells, reduced AKT phosphorylation following MTA1 knockdown further supports functional crosstalk between the BRAF and MTA1/AKT signaling pathways. Collectively, these findings identify MTA1 as a critical regulator of canine UC progression and reveal complex signaling interactions that support its potential as a therapeutic target for canine UC. Full article

Background: External and internal forces and tissue energy influence the structure and function of mammalian tissues during life in a gravitational field. Changing force (stress) and energy equilibria provide a dynamic means to regulate cell and tissue growth during development and maturation. However, genetic mutations and changes in expression of macromolecules involved in cell and extracellular matrix (ECM) equilibria lead to tumor formation. Methods: A model is presented illustrating connections between ECM, cell membranes, cell cyto- and nucleoskeletons, cell nucleus, and cell–cell junctions that promote energy storage, transmission, and dissipation. The effects of mutations involving changes in P53 and Coll 11A1 genes and changes in expression of collagens and collagen receptors, integrins, ILK, FAK, Talin, Paxillin, Kindlins, c-SRC, Actin, myosin light chain, Filamin A, E-cadherin, and beta catenin that have been reported to occur in cancerous lesions are examined. Results: When mutations or altered component expressions occur, mechanotransduction pathways are activated that lead to modified epithelial–mesenchymal (EMT) and endothelial–mesenchymal (ENT) transitions resulting in new cell division and deposition of ECM. Conclusions: It is hypothesized that changes in genes and expression of proteins in the connections between ECM and bound cells alter energy storage and dissipation. This leads to local stress concentrations that alter force and energy dynamic equilibria required to maintain homeostasis. Excess energy associated with broken connections within cells is dissipated through changes in myosin structure and function. Full article

Zoonotic bacterial pathogens are transmitted through various routes and are traditionally associated with acute febrile illnesses that may include pulmonary complications. However, in some survivors, the disease extends beyond the acute phase, leading to the remodeling of pulmonary architecture and driving progressive fibrosis. Although no direct cases have been reported, these pathogens may plausibly predispose injured lungs to carcinogenesis, similar to the well-recognized phenomenon of tuberculosis-associated scar cancer. As such long-term sequelae remain largely overlooked in current clinical practice, their potential contribution to fibrotic and malignant lung disease represents a critical and underexplored knowledge gap. This review proposes a unified mechanistic framework linking acute pathogen-mediated alveolar damage to chronic pulmonary fibrosis and subsequent lung carcinogenesis. We delineate four convergent biological pillars driving this continuum: (1) pathogen persistence establishing chronic Interleukin-1β (IL-1β)/Tumor necrosis factor-α (TNF-α)-mediated inflammation; (2) sustained TGF-β signaling and mechanotransduction driving progressive extracellular matrix remodeling; (3) unresolved reactive oxygen species (ROS) generation causing profound oxidative DNA damage; and (4) aberrant epithelial–mesenchymal transition (EMT) that perpetuates fibrosis and generates pre-malignant cell populations. Together, these sequelae alter lung biomechanics, suppress local immune surveillance, and create a mutagenic environment that is highly conductive to malignant transformation. Although direct epidemiological data remain emerging, the significant mechanistic overlap with idiopathic pulmonary fibrosis (IPF) presents a compelling rationale for shared oncogenic risk. We advocate for a paradigm shift in clinical practice, emphasizing the potential value of long-term surveillance for survivors of severe pulmonary infections. By integrating infectious diseases, pulmonology, and oncology, this framework highlights a neglected cause of fibrotic lung disease and establishes a foundation for future translational research. Full article

Head and neck squamous cell carcinoma (HNSCC) continues to be an important health problem worldwide, with high morbidity and mortality and considerable biological variability among tumors. Although clinicopathological features remain essential in clinical practice, they do not fully explain differences in tumor behavior or treatment response. The growing availability of molecular data has therefore increased interest in multi-omics strategies for HNSCC. Genomic, transcriptomic, epigenomic, proteomic, and metabolomic analyses provide different, but complementary, views of tumor biology. Genomic alterations, including recurrent changes in TP53 and PIK3CA, help define the molecular landscape of HNSCC, while transcriptomic biomarkers such as PD-L1 expression and epithelial–mesenchymal transition (EMT)-related signatures provide insights into tumor–microenvironment interactions, immune evasion, and treatment resistance. Epigenetic alterations further regulate gene expression, whereas proteomic and metabolomic biomarkers provide information more closely related to cellular function, metabolic reprogramming, and disease progression. More recently, single-cell and spatial approaches have allowed tumors to be studied according to their cellular composition and tissue organization. Artificial intelligence and machine learning are also being explored to combine these large datasets and identify biomarkers related to prognosis or therapeutic response. This review critically discusses the principal multi-omics biomarkers investigated in HNSCC, including biomarkers associated with genomic instability, immune regulation, EMT, and metabolic reprogramming, highlighting their potential clinical applications and the current barriers limiting their incorporation into routine practice. Full article

Cancer metastasis is the leading cause of cancer-related mortality, accounting for more than 90% of cancer deaths worldwide. However, the epigenetic mechanisms governing the metastatic cascade remain incompletely understood. Epigenetic reprogramming, including reversible changes in histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA (ncRNA)-mediated regulation, enables tumor cells to acquire invasive, migratory, stem-like, and immune-evasive characteristics. During epithelial-to-mesenchymal transition (EMT), key epigenetic regulators such as histone deacetylases (HDACs), the Polycomb repressive complex 2 (PRC2) subunit EZH2, lysine-specific demethylase 1 (LSD1/KDM1A), and bromodomain and extraterminal (BET) proteins repress epithelial gene expression while activating mesenchymal transcriptional programs, promoting invasion and dissemination. At distant sites, epigenetic plasticity facilitates metastatic colonization through mesenchymal-to-epithelial transition (MET) and adaptive chromatin remodeling. Because these changes are reversible, they represent attractive therapeutic targets. HDAC, EZH2, LSD1/KDM1A, BET, and DNA methyltransferase (DNMT) inhibitors have shown promise in preclinical models of metastasis, with several advancing through clinical trials. Long non-coding RNAs, particularly HOTAIR, function as epigenetic scaffolds that reinforce metastatic programs, while reciprocal interactions between tumor cells and the tumor microenvironment (TME) drive epigenetic adaptations that promote immune evasion and metastatic progression. In addition, circulating tumor DNA (ctDNA) methylation signatures are emerging as minimally invasive biomarkers for assessing metastatic risk and monitoring treatment. This review summarizes current insights into the epigenetic regulation of cancer metastasis, evaluates emerging epigenetic therapies, and highlights translational opportunities to advance precision anti-metastatic strategies and improve patient outcomes. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate below 10%. Cancer-associated fibroblasts (CAFs) promote epithelial–mesenchymal transition (EMT) and metastasis, yet the specific CAF subtypes and molecular axes driving PDAC progression remain incompletely understood. Here, using multi-omics data from PDAC samples, we identified a malignant ductal subpopulation, termed Ductal-T0, characterized by the highest EMT activity and prominent acquisition of myofibroblastic CAF (myCAF)-like transcriptional programs. Computationally, we predicted that myCAF-secreted THBS2 and FN1 engage the ITGA3/ITGB1/SDC1/SDC4 receptor axes in Ductal-T0 cells, which could activate TNF, NF-κB, TGF-β, and PI3K-AKT-signaling pathways to promote EMT. Pseudotime trajectory and velocity analyses suggested that Ductal-T0 cells exhibited the highest propensity to acquire myCAF-like features among all ductal subpopulations. Survival analysis revealed that an increased proportion of Ductal-T0 cells and elevated abundance of THBS2-ITGA3/ITGB1 and THBS2-SDC1 ligand–receptor pairs were significantly associated with poor prognosis. Spatial transcriptomics further revealed that myCAFs and Ductal-T0 cells co-localized at the tumor margin, which may contribute to reduced immune cell presence via dense extracellular matrix (ECM) barrier formation—a computationally inferred model of EMT-associated immune exclusion and metastatic progression—and identify THBS2 as a promising candidate for future therapeutic investigation to disrupt CAF–tumor crosstalk in PDAC. Full article

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent malignancy worldwide. Moreover, ESCC remains poorly characterized at the molecular level, which contributes to limited therapeutic options and an overall poor prognosis. In this context, HMGA family members, which are overexpressed in tumors but almost absent in healthy adult tissues, seem to represent promising therapeutic targets. These proteins act by binding to AT-hook DNA-binding motifs and may regulate the expression of several genes associated with tumor progression. Therefore, integrating in silico, translational, and in vitro approaches, we investigated the functional consequences of blocking HMGA2–DNA interaction in ESCC tumor progression by using netropsin, a site-specific ligand for AT-rich DNA regions. Our results demonstrate that netropsin treatment significantly reduced cell viability, migration, and cell cycle progression, thereby promoting apoptosis. Furthermore, netropsin treatment was capable of partially reverting Epithelial–Mesenchymal Transition (EMT) activation associated with HMGA2 expression, by downregulating EMT activators, such as Slug and Twist. Finally, the netropsin treatment sensitizes ESCC cells to chemotherapeutic treatment with 5-Fluorouracil. Taken together, our findings highlight that AT binding-specific blockade could be correlated with the inhibition of HMGA2 and may reveal a promising approach to better understand ESCC progression. Full article

Background: Chronic psychological stress drives metastasis in triple-negative breast cancer (TNBC), yet the underlying mechanisms remain poorly understood and effective interventions are lacking. Stress-induced expansion of myeloid-derived suppressor cells (MDSCs) and subsequent immune remodeling play critical roles, with aberrant myeloid differentiation of hematopoietic stem and progenitor cells (HSPCs) serving as a major source of MDSCs. This study investigates whether epicatechin gallate (ECG) suppresses stress-driven TNBC growth and lung metastasis by regulating HSPC myeloid differentiation. Methods: A mouse model of chronic unpredictable mild stress (CUMS) followed by 4T1 tumor implantation was used to evaluate the anti-tumor effects of ECG. CETSA-WB, molecular docking, HSPC differentiation assays, and MDSC functional validation assays, along with immunohistochemistry, immunofluorescence, and flow cytometry, were performed to elucidate how ECG modulates glucocorticoid (GC)/glucocorticoid receptor (GR) signaling and HSPC differentiation. Results: ECG dose-dependently alleviated depressive-like behaviors, reduced serum corticosterone (Cort), and inhibited tumor growth and lung metastasis. Notably, ECG decreased lung metastatic foci by 76.9% relative to the CUMS group. Mechanistically, chronic stress activated GR and induced its nuclear translocation in HSPCs, promoting aberrant HSPC-to-MDSC differentiation. ECG directly bound GR, blocked its nuclear translocation, and suppressed the myeloid differentiation of HSPCs into MDSCs, which was accompanied by downregulation of S100A8/A9, fibronectin, and MMP-2, as well as increased CD8⁺ T cell infiltration. Supernatants from ECG-pretreated and differentiated HSPCs reversed Cort-induced epithelial–mesenchymal transition (EMT) in 4T1 cells. Conclusions: ECG acts as a natural GR signaling blocker that directly targets GR to block chronic stress-driven abnormal myeloid differentiation of HSPCs, thereby remodeling the pulmonary immune microenvironment, suppressing EMT, and reducing breast cancer lung metastasis. These findings identify ECG as a promising GR signaling blocker and a potential adjuvant therapy for cancer patients under high-stress conditions. Full article

Background: Metastasis is the leading cause of mortality in lung cancer and is regulated by multiple molecular mechanisms, including microRNAs (miRNAs). Although cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT) contribute to metastatic progression, the miRNA networks underlying these phenotypes remain poorly characterized in non-small cell lung cancer (NSCLC). Aim: To identify miRNA signatures associated with CSCs and EMT in NSCLC and functionally characterize hsa-let-7a-3p. Methods: EMT was induced in A549 and NCI-H1975 cells by dCas9-mediated activation of TWIST, whereas CSC-enriched populations were generated by CD133-based sorting and stem cell culture conditions. Small RNA sequencing, bioinformatic analyses, qPCR validation, and functional assays were performed to identify and characterize phenotype-associated miRNAs. Results: Small RNA sequencing identified distinct miRNA expression profiles associated with EMT and CSC enrichment. Comparative analysis identified 13 commonly downregulated and 13 commonly upregulated miRNAs shared by CSCs from A549 and H1975 cells, suggesting conserved post-transcriptional regulatory mechanisms. Functional enrichment and miRNA–target interaction network analyses linked the miRNA signatures to pathways involved in epithelial plasticity, stemness, and tumor progression, including Wnt, TGF-β, mTOR, focal adhesion, adherens junction, and regulation of the actin cytoskeleton. Among the dysregulated miRNAs, hsa-let-7a-3p was consistently upregulated in CD133⁺ CSC-enriched cells from both NSCLC cell lines. Functional assays showed that hsa-let-7a-3p overexpression significantly reduced clonogenic capacity and showed a trend toward decreased invasion without affecting proliferation. Conclusion: This study identifies miRNA signatures associated with CSC-enriched and EMT-associated phenotypes in NSCLC and demonstrates that these signatures represent coordinated post-transcriptional regulatory programs involved in epithelial plasticity, stemness, and metastatic progression. Functional validation of hsa-let-7a-3p further supports its role as a context-dependent regulator of CSC biology and highlights the potential of miRNA signatures as diagnostic biomarkers in NSCLC. Full article

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. Full article

Breast cancer (BC) progression is strongly influenced by the extracellular matrix (ECM), whose remodelling regulates tumour growth, invasion, metastasis, immune modulation, and therapeutic response. Among ECM components, collagens have emerged as both structural proteins and active mediators of mechanotransduction, stromal interactions, and tumour cell behaviour. This narrative review analyses collagen families and collagen-associated proteins implicated in BC, integrating evidence on their expression patterns, biological functions, clinical significance, and translational potential. We examine fibrillar and non-fibrillar collagens, including fibril-associated collagens with interrupted triple helices (FACITs), membrane-associated collagens with interrupted triple helices (MACITs), basement membrane (BM) collagens, and multiplexins, together with their interactions with cancer-associated fibroblasts (CAFs), immune cells, and signalling pathways involved in tumour progression. Alterations in collagen composition, organization, crosslinking, and degradation regulate ECM stiffness, epithelial–mesenchymal transition (EMT), invasion, metastatic dissemination, and therapy resistance. Several collagen types and collagen-derived fragments also show promise as prognostic biomarkers and therapeutic targets, particularly in aggressive BC subtypes such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC). Overall, this review highlights the collagenome as a dynamic component of the breast tumour microenvironment (TME) and supports collagen-informed strategies for improved patient stratification and targeted therapies. Full article

Background: The aggressive progression of mesothelioma is driven not only by intrinsic tumor cell plasticity but also by dynamic interactions between tumor cells and the surrounding stromal microenvironment; however, the mechanisms by which stromal populations regulate epithelial–mesenchymal transition (EMT), tumor evolution, and therapeutic resistance remain unclear. Methods: We integrated longitudinal transcriptomic profiling with single-cell RNA sequencing in a murine intraperitoneal mesothelioma model spanning disease progression from week 0 to week 8 to identify stromal-EMT programs associated with tumor progression. In vitro fibroblast–tumor co-culture systems were used to assess how different fibroblast-to-tumor cell ratios influence transcriptional reprogramming and mesenchymal transition. Results: Single-cell analysis revealed marked stromal heterogeneity, identifying eight distinct cancer-associated fibroblast (CAF) subtypes: myCAF, mCAF, iCAF, TGF-βCAF, vCAF, plCAF, apCAF, and meCAF. These subsets showed specialized transcriptional programs associated with developmental signaling and metabolic adaptation. Functional analyses demonstrated coordinated intercellular communication across six interconnected modules, including mesenchymal transition, fibrotic remodeling, TGF-β/metabolic adaptation, adhesion signaling, WNT activation, and inflammatory crosstalk. Notably, mCAF, TGF-βCAF, and plCAF populations showed transcriptional convergence, suggesting cooperative formation of a desmoplastic, immunoregulatory niche. Co-culture experiments confirmed that fibroblast-derived signaling induces ratio-dependent transcriptional changes, promoting a shift from epithelioid to mesenchymal phenotypes. Conclusions: These findings highlight stromal regulation of EMT as a key driver of mesothelioma progression, sarcomatoid transition, and therapy resistance, and identify tumor–stroma signaling networks as potential therapeutic targets. Full article

Colorectal cancer (CRC) treatment with standard chemotherapeutics such as capecitabine (CAP) and irinotecan (IRT) is frequently limited by toxicity and resistance. To identify novel adjuvant strategies, we investigated the dichloromethane–methanol (DM) Soxhlet extract of the red alga Jania rubens, previously shown to exert intrinsic antiproliferative effects via reactive oxygen species (ROS) induction, inhibition of epithelial–mesenchymal transition (EMT), and suppression of TET enzymes. The present study evaluated the effect of the DM extract in combination with chemotherapeutic agents in HCT-116, Caco-2, and HT-29 colorectal cancer cell lines, assessing its potential to enhance treatment response. Co-treatment with the DM extract significantly enhanced the cytotoxic and anti-migratory effects of CAP and IRT in HCT-116 and Caco-2 cells. Combination treatment also impaired long-term clonogenic survival, suggesting the inhibition of therapy-resistant subpopulations. Flow cytometric analysis (Annexin V-FITC/PI) revealed a dose-dependent increase in apoptosis in HCT-116 cells following DM treatment. Western blot analysis further supported the pro-apoptotic activity of the DM extract by demonstrating reduced BCL-2 protein expression. The extract additionally modulated the mRNA expression levels of cytokines (TNF-α, IL-6, and IL-10), suggesting potential immunomodulatory effects in colorectal cancer cells. Notably, co-administration of IRT and the DM extract enhanced apoptosis, primarily through the downregulation of the anti-apoptotic gene BCL-2. Together, these findings indicate that the Jania rubens DM extract modulates multiple cellular pathways and enhances the response to conventional CRC chemotherapeutic agents. Full article

Cellular plasticity allows organisms to adapt dynamically to both physiological and pathological contexts. Epithelial–mesenchymal transition (EMT) is a well-known example of this plasticity and is now widely recognized as a reversible and highly dynamic spectrum of cellular states rather than a simple binary switch. In this review, we summarize current knowledge on the Hippo pathway transcriptional co-activators YAP and TAZ, focusing on their role as a central hub that integrates mechanical, biochemical and metabolic signals from the microenvironment to control cell fate reprogramming. We discuss how YAP/TAZ interact with EMT-related signaling pathways and transcriptional networks to regulate the acquisition, maintenance and dynamic remodeling of mesenchymal states, as well as hybrid epithelial/mesenchymal (E/M) phenotypes. We also highlight the presence of interconnected feed-forward and feedback regulatory loops within the YAP/TAZ–EMT axis, which contribute to the stabilization of cellular plasticity and support context-dependent transcriptional programs. These mechanisms are involved in key physiological processes, including embryonic development and tissue repair, and in pathological conditions such as organ fibrosis and cancer progression. Therefore, we propose a model where YAP/TAZ act as the central molecular hub within the networks governing cellular plasticity and EMT dynamics. Finally, we discuss how a better understanding of the mechanistic basis of YAP/TAZ-driven EMT may provide a useful framework for the development of therapeutic strategies aimed at modulating cellular plasticity in cancer, fibrotic diseases and regenerative medicine. Full article