Search Results (158)

Background: Colorectal cancer (CRC) mortality is predominantly driven by liver metastasis and poor responsiveness to chemotherapy. The histone methyltransferase SMYD3 has been implicated in oncogenic transcriptional programs; however, its downstream effectors and microenvironmental roles in CRC remain unclear. Methods: We investigated whether SMYD3 regulates the transcription and function of the membrane receptor CDCP1, which mediates Src/PKCδ signaling and promotes invasion and stromal remodeling. A combination of molecular assays, including ChIP-qPCR, Western blotting, and co-culture experiments, was employed to examine the SMYD3–CDCP1 axis and its impact on epithelial–mesenchymal transition (EMT), cancer-associated fibroblast (CAF) activation, and oxaliplatin (OXA) sensitivity. Results: SMYD3 directly bound to the CDCP1 promoter and catalyzed H3K4me3 enrichment, thereby enhancing CDCP1 transcription. Upregulated CDCP1 activated Src/PKCδ signaling, facilitating EMT and CAF activation within the tumor microenvironment. Genetic suppression of SMYD3 reduced metastatic potential and improved oxaliplatin response in vivo, while genetic or pharmacologic perturbation attenuated tumor–stroma crosstalk and enhanced oxaliplatin sensitivity in vitro. Conclusions: The SMYD3–CDCP1 axis drives CRC progression by epigenetically promoting CDCP1 transcription and remodeling the tumor microenvironment. Targeting this pathway may provide a promising therapeutic strategy to restrain metastasis and enhance chemotherapy efficacy in CRC. Full article

Background: The E26 transformation-specific (ETS) transcription factor Friend Leukemia Integration 1 (FLI1) has been linked to breast cancer aggressiveness, stromal remodeling, and immune modulation, yet the regulatory mechanisms governing its activity remain poorly defined. Of note, various studies have shown that EWS-FLI1-mediated transcription programs are facilitated via direct recruitment and binding of the NuRD-LSD1 complex, regulating its associated gene targets. Furthermore, LSD1 inhibition exhibited reverse transcriptional profiles driven by ETS-FLI and reduced in vivo tumorigenesis in cancers. Methods: We evaluated FLI1 expression across multiple invasive breast carcinoma (IBC) cohorts to determine its prognostic significance and associations with stromal features. In parallel, we investigated FLI1 regulation in humanized breast cancer mouse models treated with an LSD1 inhibitor. Results: High FLI1 expression was associated with advanced histological grade in IBC, consistent with an oncogenic function. FLI1-high tumors also exhibited elevated stromal and immune scores, indicating a role in remodeling the tumor microenvironment. Additionally, LSD1 inhibition downregulated FLI1 target genes involving angiogenesis and invasion. Conclusions: These findings highlight the dual role of FLI1: tumor-intrinsic FLI1 promotes proliferation and invasion, whereas its transcriptional regulation in tumor and endothelial compartments likely reflects LSD1 dependence. Collectively, our results support a mechanistic model in which LSD1–FLI1 crosstalk is involved in immune and stromal remodeling, positioning FLI1 as both a marker of tumor aggressiveness and a potential predictor of response to epigenetic therapies in breast cancer. Full article

Adipose tissue plays a crucial role in the tumor microenvironment (TME), where its secreted extracellular vesicles (EVs) are involved in the complex signaling between tumor cells and surrounding stromal components. This study aims to unravel the mechanisms through which adipocyte-derived EVs influence breast cancer (BC) progression. Human mesenchymal stem cells (hMSCs) were differentiated into adipocytes following a 21-day induction protocol that led to significant accumulation of lipid droplets within the cells. EVs were isolated from the conditioned medium of both hMSC-derived adipocytes and BC cells. Particle size distribution, morphology, and uptake into the recipient cell were investigated via nanoparticle tracking analysis, transmission electron microscopy, and fluorescence microscopy, respectively. Our results show that BC-derived EVs notably impaired cell viability and modulated the expression of key genes involved in apoptosis resistance within stromal cells. On the other hand, stromal-derived EVs significantly altered tumor cell behavior, indicating a dynamic, bidirectional exchange of bioactive signals. These findings underscore the pivotal role of EV-mediated communication in the tumor-stroma interplay, suggesting that adipocyte-cancer cell EV crosstalk contributes to the remodeling of the TME, potentially facilitating tumor progression. Full article

Head and neck cancer (HNC) is highly heterogeneous and difficult to treat, underscoring the need for rapid, patient-specific models. Standard three-dimensional (3D) cultures often lose stromal partners that influence therapy response. We developed a patient-derived system maintaining tumor cells, cancer-associated fibroblasts (CAFs), and cells undergoing partial epithelial–mesenchymal transition (pEMT) for drug sensitivity testing. Biopsies from four HNC patients were enzymatically dissociated. CAFs were directly cultured, and their conditioned medium (CAF-CM) was collected. Cryopreserved primary tumor cell suspensions were later revived, screened in five different growth media under 2D conditions, and the most heterogeneous cultures were re-embedded in 3D hydrogels with varied gel mixtures, media, and seeding geometries. Tumoroid morphology was quantified using a perimeter-based complexity index. Viability after treatment with cisplatin or Notch modulators (RIN-1, recombination signal-binding protein for immunoglobulin κ J region (RBPJ) inhibitor; FLI-06, inhibitor) was assessed by live imaging and the water-soluble tetrazolium-8 (WST-8) assay. Endothelial Cell Growth Medium 2 (ECM-2) medium alone produced compact CAF-free spheroids, whereas ECM-2 supplemented with CAF-CM generated invasive aggregates that deposited endogenous matrix. Matrigel with this medium and single-point seeding gave the highest complexity scores. Two of the three patient tumoroids were cisplatin-sensitive, and all showed significant growth inhibition with the FLI-06 Notch inhibitor, while the RBPJ inhibitor RIN-1 induced minimal change. The optimized scaffold retains tumor–stroma crosstalk and provides patient-specific drug response data within days after operation, supporting personalized treatment selection in HNC. Full article

Background: Breast cancer remains the most prevalent malignancy in women worldwide, characterized by remarkable genetic, molecular, and clinical heterogeneity. Traditional preclinical models have significantly advanced our understanding of tumor biology, yet consistently fall short in recapitulating the complexity of the human tumor microenvironment (TME), immune, and metastatic behavior. In recent years, breast cancer-on-a-chip (BCOC) have emerged as powerful microengineered systems that integrate patient-derived cells, stromal and immune components, and physiological stimuli such as perfusion, hypoxia, and acidic milieu within controlled three-dimensional microenvironments. Aim: To comprehensively review the BCOC development and application, encompassing fabrication materials, biological modeling of key subtypes (DCIS, luminal A, triple-negative), dynamic tumor–stroma–immune crosstalk, and organotropic metastasis to bone, liver, brain, lungs, and lymph nodes. Methods: We selected papers from academic trusted databases (PubMed, Web of Science, Google Scholar) by using Breast Cancer, Microfluidic System, and Breast Cancer on a Chip as the main search terms. Results: We critically discuss and highlight how microfluidic systems replicate essential features of disease progression—such as epithelial-to-mesenchymal transition, vascular invasion, immune evasion, and therapy resistance—with unprecedented physiological relevance. Special attention has been paid to the integration of liquid biopsy technologies within microfluidic platforms for non-invasive, real-time analysis of circulating tumor cells, cell-free nucleic acids, and exosomes. Conclusions: In light of regulatory momentum toward reducing animal use in drug development, BCOC platforms stand at the forefront of a new era in precision oncology. By bridging biological fidelity with engineering innovation, these systems hold immense potential to transform cancer research, therapy screening, and personalized medicine. Full article

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, in part due to late diagnosis and limited prognostic tools. In recent years, microRNAs, small, non-coding regulators of gene expression, have emerged as key modulators of tumor metabolism, microenvironmental crosstalk, and therapeutic response in HCC. This narrative review synthesizes evidence published from January 2000 through April 2025, focusing on four interrelated themes: (1) miRNA-driven metabolic rewiring; (2) circulating and exosomal miRNAs as diagnostic and (3) predictive biomarkers; (4) miRNA-based therapeutic strategies. We conducted a targeted PubMed search using terms related to HCC, miRNA biology, biomarkers, metabolism, and therapy, supplemented by manual reference mining. Preclinical and clinical studies reveal that loss of tumor-suppressor miRNAs and gain of oncomiRs orchestrate glycolysis, lipid and glutamine metabolism, and stromal-immune remodeling. Circulating miRNA signatures, including single- and multimarker panels, demonstrate diagnostic AUCs up to 0.99 for early-stage HCC and distinguish HCC from cirrhosis more accurately than alpha-fetoprotein. Predictively, miRNAs such as miR-21 and miR-486-3p correlate with sorafenib resistance, while tissue and exosomal miRNAs forecast recurrence and survival after curative therapy. Therapeutic manipulation, restoring tumor-suppressor miRNAs via mimics or AAV vectors and inhibiting oncomiRs with antagomirs or LNA oligonucleotides, yields potent anti-tumor effects in models, affecting cell cycle, apoptosis, angiogenesis, and immune activation. Despite technical and delivery challenges, early-phase trials validate target engagement and inform safety optimization. In this review, we highlight opportunities to integrate miRNA biomarkers into surveillance algorithms and combine miRNA therapeutics with existing modalities, charting a roadmap toward precision-guided management of HCC. Full article

Tissue-resident memory T (TRM) cells have emerged as critical sentinels in the control of cancer metastasis, yet their precise roles across different tumor types and tissues remain underappreciated. Here, we review current insights into the mechanisms governing TRM cell seeding and retention in pre-metastatic niches, their effector functions in eliminating disseminated tumor cells, and their dynamic crosstalk with local stromal and myeloid populations. Here, we highlight evidence for organ-specific variability in TRM cell-mediated immunity, discuss strategies for therapeutically harnessing these cells—ranging from vaccination and checkpoint modulation to chemokine axis manipulation—and explore their promise as prognostic biomarkers. Finally, we outline key knowledge gaps and future directions aimed at translating TRM cell biology into targeted interventions to prevent and treat metastatic disease. Full article

Intercellular mitochondrial transfer in the tumor microenvironment (TME) is a paradigm-shifting process that redefines cancer–T cell crosstalk. This review explores its dual nature as both a tumor immune evasion strategy and a promising therapeutic avenue. Crucially, oxidative stress acts as a key regulator, inducing tunneling nanotube (TNT) formation to facilitate this organelle exchange. Tumors exploit this by transferring dysfunctional, reactive oxygen species (ROS) generating mitochondria to T cells to induce senescence while simultaneously hijacking healthy mitochondria from T cells to empower their own metabolism. This directional exchange, quantified by computational tools like mitochondrial-enabled reconstruction of cellular interactions (MERCI), is linked to poor clinical outcomes. Transfer occurs via TNTs, extracellular vesicles, and direct contact. Conversely, the therapeutic transfer of healthy mitochondria from sources like mesenchymal stromal cells can revitalize exhausted T cells, improving chimeric antigen receptor T (CAR-T) cell efficacy. Clinical translation is guided by emerging biomarkers, including circulating mitochondrial DNA (mtDNA), mitochondrial haplogroups, and the tumor mitochondrial transfer (TMT) score. Harnessing this biological axis for next-generation immunotherapies requires overcoming challenges in transfer efficiency and standardization to effectively modulate the tumor redox landscape and immune response. Full article

Tensins (TNS1–4) are pivotal molecular scaffolds bridging the actin cytoskeleton to integrin-based adhesions, orchestrating signal transduction and governing cellular processes in cancer. Structurally, the N-terminal actin-binding domain (ABD) in TNS1–3 enables cytoskeletal regulation and interactions with regulators like the Rho GAP DLC1, while ABD-deficient TNS4 functions as a focal adhesion signal amplifier. Functionally, TNS1–3 exhibit context-dependent duality as tumor promoters or suppressors, dictated by tissue-specific microenvironments and signaling crosstalk. In contrast, TNS4 acts predominantly as an oncoprotein across carcinomas by stabilizing epidermal growth factor receptor (EGFR), driving epithelial–mesenchymal transition and invasion, and sustaining proliferation. Clinically, tensin dysregulation correlates with metastasis and poor prognosis: TNS2 serves as a diagnostic biomarker for gastrointestinal stromal tumors, aberrant TNS1/TNS3 expression predicts metastasis risk, and TNS4 is recurrently embedded in multi-gene prognostic signatures. This review synthesizes their structural basis, regulatory mechanisms, and clinical relevance, highlighting context-dependent switches and TNS4’s therapeutic potential. Full article

Cancer is no longer considered as an isolated event. Rather, it occurs because of a complex biological drive orchestrating different cell types, growth factors, cytokines, and signaling pathways within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most populous stromal cells within the complex ecosystem of TME, with significant heterogeneity and plasticity in origin and functional phenotypes. Very enigmatic cells, CAFs determine the progress and outcomes of tumors through extensive reciprocal signaling with different tumors infiltrating immune cells in the TME. In their biological drive, CAFs release numerous chemical mediators and utilize various signaling pathways to recruit and modulate tumor-infiltrating immune cells. The CAF-induced secretome and exosomes render immune cells ineffective for their antitumor activities. Moreover, by upregulating immune inhibitory checkpoints, CAFs create an immunosuppressive TME that impedes the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TILs). Further, by depositing and remodeling extracellular matrix (ECM), CAFs reshape the TME, which enhances tumor growth, invasion, metastasis, and chemoresistance. Understanding of CAF biology and its crosstalk with tumor-infiltrating immune cells is crucial not only to gain insight in tumorigenesis but to optimize the potential of novel targeted immunotherapies for cancers. The complex relationships between CAFs and tumor-infiltrating immune cells remain unclear and need further study. Herein, in this narrative review we have focused on updates of CAF biology and its interactions with tumor-infiltrating immune cells in generating immunosuppressive TME and resistance to cell death. Full article

Background/Objectives: Subcutaneous tumor models are widely used in colorectal cancer (CRC) research due to their experimental accessibility; however, the spatial organization and regulatory mechanisms of their tumor microenvironment remain poorly understood. Methods: Here, we applied spatial transcriptomics to systematically characterize spatial heterogeneity within MC38 subcutaneous tumors in a syngeneic mouse model. Results: We identified two spatially distinct tumor zones, partitioned by cancer-associated fibroblasts (CAFs), that differ markedly in cellular composition, oncogenic signaling, immune infiltration, and metabolic states. One zone exhibited features of TGF-β-driven extracellular matrix remodeling, immune exclusion, and hyperproliferative metabolism, while the other was enriched for immunosuppressive macrophages, metabolic reprogramming via PPAR and AMPK pathways, and high-risk cell populations. Spatially resolved cell–cell communication networks further revealed zone-specific ligand–receptor interactions—such as ANGPTL4–SDC2 and PROS1–AXL—that underpin stromal remodeling and immune evasion and are associated with patient prognosis. Conclusions: Collectively, our study uncovers how region-specific cellular ecosystems and intercellular crosstalk establish prognostically divergent niches within subcutaneous CRC tumors, offering insights into spatially guided therapeutic strategies. Full article

Background: Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality despite advances in treatments, necessitating more effective therapeutic strategies. Single-cell RNA sequencing (scRNA-seq) technology has revolutionized our ability to dissect the cellular complexity of cancers, which is often obscured in conventional bulk transcriptomic experiments. Methods: In this study, we performed an integrative analysis of scRNA-seq data from multiple LUAD patient cohorts to investigate cell-type-specific transcriptomic changes across disease stages. Clustering, lineage trajectory analysis, and transcriptional regulatory network reconstruction were employed to identify stage-specific gene markers and their upstream regulators. Additionally, we constructed intercellular communication networks to evaluate signaling changes within the tumor microenvironment (TME) during LUAD progression. Results: Our analysis revealed that epithelial cells from stage IV tumors exhibited a distinct transcriptional profile compared to earlier stages, a separation not observed in immune or stromal cell populations. We identified a panel of gene markers that differentiated epithelial cells across disease stages and effectively stratified patients into subgroups with distinct survival outcomes and TME compositions. Regulatory network analysis uncovered key transcription factors, including ATF3, ATF4, HSF1, KLF4, and NFIC, as potential upstream regulators of these stage-specific genes. Moreover, cell–cell communication analysis revealed a significant increase in signaling originating from epithelial cells and a concomitant decrease in immune-derived signals in late-stage LUAD. We identified several signaling pathways enriched in stage-specific crosstalk, including Wnt, PTN, and PDGF pathways, which may play critical roles in LUAD progression. Conclusions: This study provides a comprehensive single-cell resolution map of LUAD progression, highlighting epithelial-driven regulatory programs and dynamic intercellular communication within the TME. Our findings uncover novel molecular markers and regulatory mechanisms with potential prognostic and therapeutic value for more precise treatment. Full article

Lactate is a key oncometabolite that plays a critical role in modulating the behavior and function of both tumor cells and tumor-associated stromal cells within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), as essential stromal components, engage in dynamic crosstalk with tumor cells through lactate-mediated signaling pathways. Elevated lactate levels in the TME primarily originate from metabolic reprogramming in tumor cells and CAFs. Notably, tumor-derived lactate not only promotes basement membrane remodeling and epithelial–mesenchymal transition (EMT) in CAFs but also influences their functional phenotype. Conversely, CAF-secreted lactate significantly contributes to tumor progression. Therapeutic strategies targeting lactate transport and metabolism—particularly through the inhibition of monocarboxylate transporters (MCTs) and lactate dehydrogenase (LDH)—have emerged as promising approaches in cancer treatment. This review summarizes the multifaceted roles of lactate and lactylation, elucidates the molecular mechanisms underlying lactate-mediated tumor–CAF crosstalk, and explores potential therapeutic interventions targeting lactate metabolism and CAFs. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis, and its progression is driven by epithelial plasticity and tumor microenvironment remodeling. Finding biomarkers that are responsible for the turning point from the early stage to the aggressive phase would facilitate clinical management. Method: In this study, we employed single-cell RNA sequencing to characterize a distinct subpopulation of highly proliferative epithelial cells undergoing a transitional phase during PDAC progression. By linking to cell cycle dysregulation, epithelial differentiation, and clinical staging, we constructed a gene-based risk score model using Lasso Cox regression. The expression of selected genes within the model was further validated using qPCR. Results: The model demonstrated robust predictive power for patient prognosis, TNM staging, and chemotherapy sensitivity. Further analysis of the tumor microenvironment revealed intensified crosstalk between a specific fibroblast subpopulation and transitional epithelial cells, mediated largely by collagen signaling. This stromal–epithelial interaction was found to contribute to the fibrotic barrier characteristic of PDAC. Additionally, immune profiling uncovered altered infiltration patterns, particularly involving natural killer (NK) cells in high-risk patients, suggesting mechanisms of immune tolerance and inhibition. Conclusions: These findings offer potential avenues for early detection, risk stratification, and targeted therapeutic strategies in PDAC. Full article

Aberrant activation of the Hedgehog (Hh) signaling pathway can be observed in various malignancies, particularly in stroma-rich tumors like pancreatic ductal adenocarcinoma (PDAC). In PDAC, Hh signaling is thought to foster an abundant stroma, making it an appealing target for stoma-targeted therapy. However, the use of Hh antagonists in the clinic has thus far not been successful. To reassess the clinical merit of Hh-targeted therapy in PDAC, we sought to better characterize the role of Hh signaling in tumor-stroma crosstalk. Here, we show that Hh ligands are not prognostic per se in PDAC, despite being associated with the favorable classical molecular subtype. Perturbing Hh ligand expression in PDAC cells can effectively alter their trans-signaling capacity but does not impact tumor growth in vivo. However, co-injecting PDAC cells with Smo-proficient MEFs resulted in a significant reduction in xenograft growth, suggesting that Hh-related effects on tumor growth are largely mediated through the stroma. By analyzing transcriptomic sequencing data from co-cultures, comprising human PDAC cells and mouse fibroblasts treated with a Hh-blocking antibody, we could identify stromal hits that are responsive to Hh ligands. We then leveraged the obtained set of genes to allow patient stratification based on stromal response to Hh ligands. We believe that a subset of PDAC patients may benefit from the use of Hh-targeted therapies and thereby encourage the use of our stratification tool to guide their use in PDAC clinical care. Full article