Journal of Cell Communication and Signaling最新文献

Cancer remains a major global health challenge, with high prevalence and mortality rates emphasizing the urgent need for innovative treatment strategies. Although precision oncology offers tailored therapies based on genetic profiles, the clinical translation of genomic insights has been slow. Drug repurposing, using existing FDA-approved drugs for new indications, presents a cost-effective and time-efficient alternative. This study investigates MGAM as a potential direct target of alpha-glucosidase inhibitors in colorectal cancer (CRC), explores its biomarker potential, and evaluates gene expression patterns across diverse cancers. Using RNA-Seq data from Recount3, Firebrowse, and gene set co-expression analysis databases, we analyzed the differential expression of MGAM and its paralog MGAM2 across 33 cancer types. We examined mutation profiles, methylation status, survival impact, immune cell infiltration, and drug-mRNA interactions. Validation was performed via real-time PCR and whole-exome sequencing (WES) in CRC patients. MGAM and MGAM2 showed differential expression across multiple cancers, with MGAM2 upregulated and MGAM downregulated in gastrointestinal tumors. Both genes were linked to key cancer-related pathways, including metabolism, apoptosis, cell cycle regulation, and epithelial-mesenchymal transition. MGAM exhibited frequent mutations and aberrant methylation in several cancers. Their expression correlated with immune cell infiltration and drug sensitivity, highlighting potential for therapy planning. Diagnostic modeling showed over 80% accuracy. In CRC patients, MGAM downregulation was confirmed in 64 samples, and WES revealed a novel MGAM mutation (rs2960746). These findings underscore MGAM and MGAM2 as promising biomarkers and therapeutic targets, supporting their relevance in advancing personalized oncology.

This study investigates the impact of the CD2–CD58 signaling axis on effector T cell function and tumor metabolic crosstalk in breast cancer brain metastasis (BCBM) using single-cell transcriptomic analysis. scRNA-seq data analysis revealed the critical role of CD2–CD58 signaling between CD8⁺ T cells and tumor cells in BCBM. Functional assays demonstrated that CD2 knockdown inhibited cytotoxic T lymphocyte (CTL) proliferation, activation, and cytotoxicity, leading to impaired tumor cell recognition and enhanced proliferation, migration, and invasion. In vivo studies showed that CD2-deficient CTLs promoted tumor growth and brain metastasis while affecting metabolic reprogramming by altering key enzyme expressions in pyrimidine biosynthesis and arginine metabolism pathways. The findings suggest that CD2 enhances CTL function against tumor cells and influences their metabolic states, highlighting the role of CD2 in remodeling the brain metastatic microenvironment in breast cancer.

Cancer cells can release extracellular vesicles (EVs) of different sizes under stress conditions. Among the EVs, microvesicles (MVs), which have a size between 50 and 1000 nm, are bounded by a membrane lipid bilayer, exhibit proteins at their surface, and enclose some soluble proteins. MVs can interact with surrounding cells present in the tumor microenvironment to favor tumor resistance. Indeed, they can transport some oncoproteins such as epidermal growth factor receptor (EGFR) and modify phenotype of endothelial cells (ECs). Even if their role in cell communication is well established, the understanding of anticancer treatments on their release and their protein content change are of particular importance. In this work, we showed that head and neck squamous cell carcinoma (HNSCC) cells exposed to cetuximab, monoclonal antibody targeting EGFR, can modulate EGFR expression of MVs. Moreover, this work emphasizes the effect of cetuximab on the shedding and content of MVs by HNSCC cells as well as their interaction with ECs. Consequently, MVs can be used as surrogate markers for predicting the efficacy of anti-EGFR therapies. Finally, the release of MVs after treatment must be envisaged as a resistance mechanism and must be considered in the future to evaluate the effect of therapy on the tumor microenvironment.

Circular RNAs (circRNAs) have emerged as pivotal regulators of the Notch signaling pathway, influencing diverse pathological processes ranging from cancer to neurodegenerative disorders. This review synthesizes evidence demonstrating how circRNAs modulate Notch activity through miRNA sponging (e.g., circ-NOTCH 1 promoting gastric cancer metastasis via miR-637/apelin axis), protein interactions, and peptide encoding. Key examples of oncogenic circRNAs are circNFIX (glioma) and circ-ASH2L (pancreatic cancer), which drive tumor progression by sponging miR-34a-5p, elevating NOTCH 1 expression, and activating downstream effectors. We also discuss tissue-specific duality of circRNAs. In fact, Notch signaling exhibits context-dependent roles, with circFBXW7 suppressing NOTCH 1 in T-ALL (tumor suppressor) versus circ-NSD2 activating JAG1/NOTCH 1 in colorectal cancer (oncogene). While circRNAs like hsa_circ_0001741 show prognostic promise, challenges persist in delivery and target specificity due to miRNA pleiotropy. By integrating mechanistic insights with preclinical examples, this review highlights circRNAs as both biomarkers and therapeutic targets, urging further research to address clinical translation barriers.

Biomolecular condensates are a quickly emerging area of research that strongly impacts how we view the inner workings of the cell itself. Here, we explore the connection between the Notch signaling pathway and nuclear condensate localization. In this study, we hypothesize that activated Notch intracellular domain (NICD) fragments differentially localize into unique nuclear condensates. Using both overexpression and endogenous systems, our results reveal that N1ICD, N2ICD, and N4ICD efficiently localize into subnuclear bodies, whereas N3ICD inefficiently localizes into similar subnuclear puncta. These “notchosomes” appear to be unique because they do not colocalize with markers for other known nuclear puncta. In contrast, we find that N1ICD does colocalize with other known Notch-interacting proteins, including MAML-1, RBPj, AES1, and SKIP1, but not NACK1. Through deletion analysis of the N1ICD C-terminal tail, we identify multiple regions of mouse N1ICD that are necessary for localization into notchosomes, including sequences immediately C-terminal to the ankyrin domain and sequences within the transactivation domain. We also show that N1ICD localization into notchosomes may be important for N1ICD transcriptional activity from some, but not all, Notch-responsive promoters. Collectively, our results show that Notch NICD domains form nuclear localized biomolecular condensates that may be important for transcriptional activity.

Most advanced non-small cell lung cancer (NSCLC) patients have metastasis, which poses great risks to their survival. As the most abundant components in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) can induce epithelial–mesenchymal transition (EMT) to promote tumor. This study aimed to explore the potential molecular mechanisms of CAFs-mediated EMT in NSCLC. The gene expression was assessed using RT-qPCR, immunofluorescence, and Western Blot. Cells phenotypes were evaluated through CCK-8, scratch, and transwell assays, respectively. Lactate levels were measured with a commercial kit. The m6A level of zinc finger protein 384 (ZNF384) was measured using methylated RNA immunoprecipitation. The molecular interactions was checked using chromatin immunoprecipitation and dual luciferase reporter assay. ZNF384 was upregulated in NSCLC. ZNF384 knockdown suppressed NSCLC cell proliferation and inhibited EMT-related protein vimentin and Snail, but elevated E-Cadherin. Mechanistically, CAFs-secreted lactate promoted the H3K18 lactylation of methyltransferase-like 3 (METTL3) promoter region and further increased the m6A modification of ZNF384. ZNF384 promoted the transcription of RNA polymerase III subunit G (POLR3G) by binding to POLR3G promoter region. CAFs induced EMT in NSCLC cells by enhancing ZNF384 expression. Additionally, POLRG3 silencing counteracted the promoting effect of ZNF384 overexpression on EMT in NSCLC. CAFs facilitating cell proliferation and EMT by modulating the METTL3/ZNF384/POLR3G axis. It is suggested that CAFS-related TME could be an approach for treating NSCLC.

Chondrocyte abnormalities play an important role in osteoarthritis (OA), and forkhead box C1 (FOXC1) expression is related to OA progression. Nonetheless, the molecular mechanisms underlying the action of FOXC1 in chondrocytes remain unclear. Rats were subjected to anterior cruciate ligament transection (ACLT) to establish an in vivo OA model, and chondrocytes were subjected to interleukin (IL)-1β to establish an in vitro OA model. Pathological changes in rat cartilage tissues were evaluated using hematoxylin–eosin and safranin O staining. H3K27Ac enrichment in the FOXC1 promoter was analyzed using chromatin immunoprecipitation. Interactions between EP300 and Y-box binding protein 1 (YBX1) were validated using RNA immunoprecipitation and RNA pull-down assay. The expression of YBX1, EP300, and FOXC1 was elevated in ACLT rats and IL-1β-induced chondrocytes. FOXC1 knockdown inhibited apoptosis and inflammatory response in IL-1β-induced chondrocytes. EP300 bound to FOXC1 promoter and promoted H3K27Ac enrichment in the FOXC1 promoter. Additionally, YBX1 bound to EP300 mRNA and enhanced EP300 mRNA stability. YBX1 overexpression promoted cell apoptosis and inflammation of IL-1β-induced chondrocytes, but was reversed by FOXC1 downregulation. YBX1 enhances EP300 mRNA stability and elevates FOXC1 expression by mediating FOXC1 H3K27Ac to promote IL-1β-induced chondrocyte apoptosis and inflammation, thereby exacerbating chondrocyte injury in OA.

Ovarian cancer (OC) is one of the most common malignant tumors in women, with immunotherapy resistance (ITR) being a major challenge. Glycolytic metabolic reprogramming has been shown to play a crucial role in the tumor immune microenvironment and immune evasion, yet the underlying mechanisms remain unclear. This study aims to investigate the role of Ubiquitin D (UBD) in OC immunotherapy, particularly its regulation of macrophage polarization through glycolytic metabolism. Using data from the Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases, combined with proteomics techniques, we analyzed the expression of UBD in OC tissues and its correlation with key glycolytic enzymes. Through lentiviral-mediated gene manipulation and in vivo mouse models, we evaluated the effects of UBD on macrophage polarization, glycolytic metabolism, and immunotherapy. The results indicate that UBD promotes M2 macrophage polarization through glycolytic reprogramming, enhancing immune evasion and ITR in OC. Inhibiting UBD or targeting glycolytic pathways may provide new strategies for improving OC immunotherapy.

Autophagy and inflammasomes are essential cellular mechanisms that maintain homeostasis, regulate immune responses, and influence disease progression, especially in cancer. Autophagy, a lysosome-mediated process, removes damaged organelles and misfolded proteins, allowing cells to adapt to stress. This involves autophagosome formation, fusion with lysosomes, and subsequent degradation of cellular cargo. In contrast, inflammasomes are multiprotein complexes of the innate immune system that detect pathogenic signals and cellular stress, initiating inflammatory cytokine release to facilitate tissue repair. Notably, both pathways play dual roles in cancer: Although they help preserve cellular integrity and suppress tumorigenesis, they may also promote tumor survival under adverse conditions. This review explores the molecular mechanisms underlying autophagy and inflammasome activity, emphasizing their complex interplay and regulatory networks within the tumor microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) depends a lot on how it uses glutamine to grow quickly and stay alive. Oncogenic drivers such as KRAS, c-Myc, and HIF-1α increase how much glutamine gets taken up and broken down. Meanwhile, the bacteria in the gut and tumor itself also affect how much glutamine is available throughout the body and near the tumor. This impacts both how the tumor grows and how the immune system can detect and respond to it. Multiple strategies have emerged to disrupt this dependence: glutamine antagonists (DON and its prodrugs DRP-104, JHU-083), small-molecule glutaminase inhibitors (CB-839), antibody–drug conjugates targeting the ASCT2 transporter, and combination regimens pairing glutamine blockade with immune checkpoint inhibitors. Nanoparticle formulations—including pH-sensitive and PEGylated liposomes co-delivering DON and gemcitabine—enable targeted delivery and reduce off-target toxicity. Single-agent treatments do not work so well because the cells can adapt. They boost enzymes such as asparagine synthetase and increase how they burn fatty acids to make up for the lack of glutamine. To overcome these escape routes, future interventions must concurrently target compensatory pathways and integrate biomarker-driven patient selection. Combining glutamine-targeted agents with inhibitors of asparagine synthesis or lipid oxidation, guided by multi-omics profiling, promises a more durable therapeutic benefit and lays the groundwork for personalized treatment of PDAC.