Cell Communication and Signaling最新文献

{"title":"Crosstalk between tumor endothelial cells and cancer cells is important for metastasis initiation.","authors":"Victor Oginga Oria, Joana Leitao Castro, Jéssica de Pina Roque, Alejandro Gutierrez Martinez, Freia Isak Jørgensen, Marie Vestergaard Lukassen, Leonor Rib, Mia Kristine Grønning Høg, Kasper Johansen Mygind, Janine Terra Erler","doi":"10.1186/s12964-025-02441-3","DOIUrl":"https://doi.org/10.1186/s12964-025-02441-3","url":null,"abstract":"<p><strong>Background: </strong>Metastasis is a major contributor of cancer-related mortality and involves complex crosstalk between cancer cells and stromal cells modulated by various cytokines and growth factors. While the endothelium is essential for supplying nutrients and oxygen, little is known about its role in metastasis initiation. Determining the effect of endothelial-derived angiocrine factors on cancer cells may explain the mechanisms regulating metastasis initiation.</p><p><strong>Results: </strong>In this study, we investigated the role of normal endothelial cells (NEC) and tumor endothelial cells (TEC) in regulating the rate-limiting steps of metastasis initiation. First, we demonstrated that TEC have a higher proliferation, migration, and angiogenic potential than NEC. TEC-conditioned media significantly promoted chemotaxis, invasion, and proliferation of cancer cells relative to NEC-conditioned media. Additionally, TEC facilitated faster cell-cell adhesion to tumor cells than NEC. Mass spectrometry analysis of endothelial cell secretome revealed higher levels of PDGF-AA, PDGF-C, and VEGFA in TEC-conditioned medium, which were associated with enriched PI3K-AKT, MAPK, and RAS signaling pathways, as well as regulation of actin cytoskeleton and focal adhesion. In vitro functional studies using recombinant proteins showed that PDGF-AA and PDGF-C significantly promoted cancer cell chemotaxis and invasion without affecting proliferation. However, unlike VEGFA, PDGF-AA and PDGF-C did not affect endothelial cell tube formation or vascular permeability. Interestingly, neutralization of TEC-derived PDGF-C signficantly inhibited tumor cell chemotaxis and invasion, and attenuated EphA2/AKT/P38/ERK signaling in vitro. In vivo, the co-injection of TEC and 4T1 cells resulted in significantly higher primary breast tumor growth and liver metastasis in an orthotopic mouse model.</p><p><strong>Conclusion: </strong>Our results demonstrate that crosstalk between cancer cells and TEC, partly through angiocrine factors in the TME, induces the rate-limiting steps of metastasis initiation.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"443"},"PeriodicalIF":8.2,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol oxidase treatment impairs CXCR4-mediated T cell migration.","authors":"Sofía R Gardeta, Eva M García-Cuesta, Blanca Soler Palacios, Rosa Ayala Bueno, Adriana Quijada-Freire, Noelia Santander Acerete, José Miguel Rodríguez-Frade, Mario Mellado","doi":"10.1186/s12964-025-02392-9","DOIUrl":"https://doi.org/10.1186/s12964-025-02392-9","url":null,"abstract":"<p><strong>Background: </strong>Cholesterol, a key component of mammalian cell membranes, modulates the properties of the lipid bilayer and influences the conformational states of membrane receptors, including G protein-coupled receptors (GPCRs). These effects are mediated through direct interactions with specific residues within the transmembrane regions and modulation of the surrounding lipid bilayer. Chemokine receptors, a GPCR sub-family, adopt distinct conformations associated with specific cell functions. For example, CXCL12 triggers receptor clustering, essential for directional cell migration. However, the precise mechanisms by which cholesterol controls the spatial organization of these receptors remain unclear. This study investigated the role of cholesterol in modulating the chemokine receptor CXCR4.</p><p><strong>Methods: </strong>We used lipidomic analysis to measure cellular cholesterol levels, and raster image correlation spectroscopy to assess the impact of cholesterol depletion on membrane fluidity. CXCR4 nanoclustering and dynamics were examined using single-particle tracking in TIRF mode. CXCR4 dimer formation was evaluated by FRET and FLIM analyses, and directed cell migration was measured using microfluidic chemotaxis chambers. Receptor expression and ligand binding were determined by flow cytometry with specific antibodies and CXCL12-ATTO700. Additional assays included calcium flux, and western blotting for signaling molecules. Statistical analysis used unpaired t-tests, one-way ANOVA, and two-tailed Mann-Whitney tests.</p><p><strong>Results: </strong>Our findings demonstrate that moderate cholesterol depletion using cholesterol oxidase increases membrane fluidity, impairs T cell migration towards CXCL12 gradients, and enhances CXCL12-mediated β1-integrin activation. This treatment also induced alterations in CXCR4 conformation and spatial distribution, without significantly affecting ligand binding or other chemokine-mediated signaling pathways. Immunocytochemical analysis indicated that cholesterol oxidase primarily affected the largest CXCR4 clusters, with no significant impact on lipid-enriched microdomains.</p><p><strong>Conclusions: </strong>This study identifies cholesterol as a crucial regulator of CXCR4 lateral mobility and spatial organization, enabling cells to effectively sense chemoattractant gradients.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"444"},"PeriodicalIF":8.2,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GFRAL-Fc disarms GDF15 to reprogram tumor immunity and amplify PD-1 efficacy in hepatocellular carcinoma.","authors":"Gege Shi, Wangqian Zhang, Fei Xie, Jiaxin Shi, Minghui Yan, Lei He, Zhaozhao Li, Yang Xiao, Duo Yu, Haiyan Cao, Haichen Du, Yueyuan Qiu, Kuo Zhang, Shuning Wang, Meng Li, Jieyu Zhang, Zhaowei Wang","doi":"10.1186/s12964-025-02427-1","DOIUrl":"https://doi.org/10.1186/s12964-025-02427-1","url":null,"abstract":"<p><strong>Background: </strong>Checkpoint inhibitors have revolutionized hepatocellular carcinoma (HCC) treatment, yet their efficacy remains limited in advanced stages, with suboptimal objective response rates. Growth differentiation factor 15 (GDF15), a dual-functional cytokine implicated in tumor progression and immunosuppression, represents a promising therapeutic target. This study aims to develop a novel GDF15-targeted strategy to improve HCC management and synergize with PD-1 blockade.</p><p><strong>Methods: </strong>GFRAL-Fc fusion proteins were generated by fusing the extracellular domain of GFRAL with IgG1 Fc. The anti-tumor efficacy and the anti-cachexia ability of GFRAL-Fc was evaluated in a spontaneous HCC model on GDF15 humanized mice. Additionally, the half-life and drug safety were evaluated in mice. To investigate the underlying mechanisms, a CyTOF analysis was utilized to analysis the immunoregulation effects of GFRAL-Fc within HCC. Finally, the anti-tumor effects of GFRAL-Fc in combination with Programmed Death-1 (PD-1) inhibitors were assessed.</p><p><strong>Results: </strong>GFRAL-Fc targets GDF15 to simultaneously prevent GDF15-CD48 interaction-driven ERK activation and block GDF15-GFRAL binding. Treatment with GFRAL-Fc achieved dual antitumor effects: reducing tumor progression and attenuating cancer-associated cachexia. Combination with PD-1 blockade further enhanced antitumor efficacy, resulting in a substantial decrease in tumor nodules. Mechanistic studies revealed that GFRAL-Fc reprograms the immunosuppressive tumor microenvironment by suppressing Treg activation while enhancing CD8⁺ T cell cytotoxicity.</p><p><strong>Conclusions: </strong>Our findings validate GDF15 targeting as a viable strategy to overcome checkpoint inhibitor resistance in HCC. The GFRAL-Fc fusion protein demonstrates multimodal therapeutic benefits through metabolic regulation and immune remodeling, providing a clinically translatable approach to optimize PD-1-based regimens. This study addresses critical gaps in current HCC management and warrants further clinical validation.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"440"},"PeriodicalIF":8.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical implications of ctDNA-based minimal residual disease detection in newly diagnosed peripheral T-cell lymphoma: a single-center cohort study.","authors":"Jin-Hua Liang, Wei Hua, Hua Yin, Yue Li, Xin-Yi Zhang, Jun-Heng Liang, Liu-Qing Zhu, Rui Gao, Chen-Xuan Wang, Yang Shao, Bi-Hui Pan, Xin-Yu Zhang, Jia-Zhu Wu, Qiu-Xiang Ou, Jian-Yong Li, Hao-Rui Shen, Li Wang, Wei Xu","doi":"10.1186/s12964-025-02438-y","DOIUrl":"https://doi.org/10.1186/s12964-025-02438-y","url":null,"abstract":"<p><p>Circulating tumor DNA (ctDNA) has been recognized as a promising tumor-specific biomarker, but its molecular features in peripheral T cell lymphoma (PTCL) have not been well explored. We investigated the translational significance of liquid biopsy in a uniformly treated PTCL cohort (N=64). Our study found that pretreatment ctDNA burden was strongly associated with clinical risk factors and identified as a superior predictor of progression-free survival and overall survival. Although 46.9% of patients achieved complete response at the end of therapy (EOT), only 25.9% achieved negative minimal residual disease (MRDend-) and demonstrated superior prognosis. These findings suggests that MRD status at EOT may be a critical factor in disease progression and recurrence for PTCL patients. Additionally, the most frequently altered genes were identified as TET2 (6.7%), DNMT3A (48.5%), RHOA (27.3%), and TP53 (15.2%), which were not cleared by first-line CHOP-like regimens. Most importantly, clonal evolution was displayed during induction therapy and follow-up across all histological subtypes of PTCL patients.These findings support that EOT MRD status could serve as an important prognostic marker for PTCL patients and clear the direction of exploration and selection the new drugs particularly targeted to TET2/DNMT3A/RHOA mutation integrating with conventional treatments for PTCL patients.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"441"},"PeriodicalIF":8.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular cargo of small EVs from NSCLC patient BALF and plasma: unveiling their role in airway inflammation and immune regulation in a novel human 3D bronchial model.","authors":"Magdalena Dlugolecka, Jacek Szymanski, Lukasz Zareba, Karolina Soroczynska, Zuzanna Homoncik, Malgorzata Polubiec-Kownacka, Ewa Frankiewicz, Diana Wierzbicka, Kannathasan Thetchinamoorthy, Joanna Domagala-Kulawik, Malgorzata Czystowska-Kuzmicz","doi":"10.1186/s12964-025-02423-5","DOIUrl":"https://doi.org/10.1186/s12964-025-02423-5","url":null,"abstract":"<p><strong>Background: </strong>Tumor-derived small extracellular vesicles (EVs) play a crucial role in modulating immune responses and shaping the tumor microenvironment; however, their functional impact on airway immunity in NSCLC remains largely unexplored. This study represents the first attempt to investigate the immunomodulatory and tumor-promoting effects of NSCLC-derived EVs in a human 3D bronchial airway model, which closely mimics the human lung microenvironment.</p><p><strong>Methods: </strong>EVs were isolated from the plasma and bronchoalveolar lavage fluid (BALF) of NSCLC patients and analyzed via nanoparticle tracking analysis (NTA) and high-resolution imaging flow cytometry. The lymphocyte compositions of the matched blood and BALF samples were profiled. To assess the functional effects of EVs, we employed a pioneering in vitro 3D airway coculture model that combines primary human airway epithelial cells and alveolar macrophages at the air‒liquid interface. Proteomic analysis of EV-treated cells and their secretome was performed to identify key molecular pathways underlying EV-driven immunomodulation.</p><p><strong>Results: </strong>Surprisingly, no significant molecular differences were detected between EVs from cancerous (cBALF) and opposite (oBALF) lung compartments, despite a localized increase in regulatory T cells (Tregs) in the cBALF, suggesting regional immunosuppression. Plasma-derived EVs exhibited highly diverse, patient-specific molecular signatures but were not directly correlated with clinical or immune parameters. Functional studies of EVs with high and low surface molecular cargo in a 3D airway model revealed that both EV subgroups promoted monocyte/macrophage recruitment, angiogenesis, and epithelial-to-mesenchymal transition (EMT) via MCP-1 secretion and induced an immunosuppressive airway microenvironment, enhancing IL-10 production and shifting macrophages toward a tumor-promoting M2 phenotype. Proteomic analysis revealed distinct differentially expressed protein (DEP) profiles across epithelial and macrophage populations, ultimately resulting in protumorigenic and immunosuppressive outcomes. Notably, functional enrichment analysis of macrophages revealed that EV-driven M2 polarization occurred through the suppression of EGFR activity, a previously underrecognized mechanism that links EV-mediated immune suppression to lung cancer progression.</p><p><strong>Conclusions: </strong>This study provides the first functional evidence that NSCLC-derived EVs drive immune suppression and tumor-supportive changes in a human 3D airway model, closely mimicking in vivo lung conditions. The identification of EGFR suppression as a driver of macrophage polarization underscores the need to consider macrophage-specific EGFR regulation in anti-EGFR therapies to prevent unintended protumorigenic effects. These findings pave the way for future studies exploring EV cargo, such as miRNAs, as potential therapeutic targets in NSCLC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"442"},"PeriodicalIF":8.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Taming fatty liver: can taurine combat metabolic dysfunction in MASLD?","authors":"Lin Meng, Fayu Lu, Bing Zhang, Yujia Ma, Jian Gao","doi":"10.1186/s12964-025-02439-x","DOIUrl":"https://doi.org/10.1186/s12964-025-02439-x","url":null,"abstract":"<p><p>Metabolic dysfunction associated with steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, significantly impacting human health and imposing substantial socioeconomic burdens. Characterized by excessive lipid accumulation in the liver, MASLD can progress to non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). Despite extensive research, the molecular mechanisms underlying MASLD remain incompletely understood, and no effective pharmacological treatments have been approved. This review explores the potential mechanisms of MASLD pathogenesis, early diagnostic approaches, and the promising role of taurine in mitigating MASLD progression via the gut-liver axis. As research advances, taurine may offer a novel therapeutic avenue, presenting new possibilities for effective clinical interventions in MASLD management.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"439"},"PeriodicalIF":8.2,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enabling mechanistic studies of EVs in vivo: a protocol for isolation and cell-specific labelling in larval zebrafish.","authors":"Ezgi Kiyga, Katy Reid, Guillaume van Niel, Julie Mazzolini, Dirk Sieger","doi":"10.1186/s12964-025-02433-3","DOIUrl":"10.1186/s12964-025-02433-3","url":null,"abstract":"<p><strong>Background: </strong>Extracellular vesicles (EVs) are critical mediators of intercellular communication in development, physiology, and disease. In vivo models such as Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio (zebrafish) now provide powerful platforms to visualize EV dynamics in real time. However, the full potential of these models remains underutilized due to the lack of reliable, cell-specific EV labelling tools and robust EV isolation protocols. Here, we present an optimized workflow for the isolation of EVs from zebrafish larvae and the in vivo labelling of EVs in a cell-type-specific manner.</p><p><strong>Methods: </strong>To isolate EVs from larval zebrafish, we used size exclusion chromatography (SEC). By comparing different tissue digestion methods and performing step-by-step optimisation of sample preparation prior to SEC, we established a novel protocol that enables EV isolation without compromising cell viability. EV size and concentration were assessed by nanoparticle tracking analysis (NTA), with subsequent characterization by transmission electron microscopy (TEM) and Western blotting. To evaluate the sensitivity of our protocol, we treated zebrafish larvae with GW4869, a known inhibitor of EV biogenesis, and assessed the dose-dependent effects on EV release. To specifically label EVs from distinct cell types, we have generated a UAS: CD63-GFP construct which can be expressed under control of the Gal4 transcriptional activator.</p><p><strong>Results: </strong>Through a systematic comparison of tissue dissociation techniques, we identify Bacillus licheniformis protease as a superior alternative to conventional collagenase treatment, which compromises cell integrity. Treatment with GW4869 confirmed that EV biogenesis and release can be inhibited in a dose-dependent manner and demonstrated that our protocol is sensitive enough to detect and quantify changes in EV levels. To enable cell-specific EV tracking in vivo, we combined the UAS: CD63-GFP construct with a radial glia-specific Gal4 driver line, providing a proof-of-concept for targeted EV imaging in intact tissues.</p><p><strong>Conclusions: </strong>These advances provide a versatile toolkit for mechanistic studies of EV function in vivo. The broad availability of cell-type-specific Gal4 driver lines in zebrafish and Drosophila will now allow researchers to trace EV dynamics from virtually any cell type, while our isolation protocol enables rigorous, quantitative EV analyses across developmental and pathological contexts.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"436"},"PeriodicalIF":8.2,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145294435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate shuttle between cytotrophoblast and syncytiotrophoblast in the placenta enhances ferroptosis resistance and maintains placental homeostasis: implications for early pregnancy loss.","authors":"Yuelin Zhu, Qianqian Li, Xin Yu, Yun Yang, Qian Yang, Yongqing Wang, Xuan Shao, Yan-Ling Wang","doi":"10.1186/s12964-025-02450-2","DOIUrl":"10.1186/s12964-025-02450-2","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"438"},"PeriodicalIF":8.2,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145294470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial ribosomal protein L12 mediates metabolic reorganization in clear cell renal cell carcinoma by regulating mitochondrial biosynthesis.","authors":"Shengnan Sun, Dun Su, Tianyi Dong, Bo Wang, Xingzhao Ji, Lingju Chu, Shicong Lu, Tianyi Zhang, Xiaoming Sun, Yi Liu, Qiang Wan","doi":"10.1186/s12964-025-02375-w","DOIUrl":"10.1186/s12964-025-02375-w","url":null,"abstract":"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC) is characterized by mitochondrial dysfunction and the Warburg effect, which refers to enhanced aerobic glycolysis. Mitochondrial ribosomal protein 12 (MRPL12) plays a pivotal role in mitochondrial biogenesis by promoting mitochondrial transcription through its interaction with POLRMT. Our previous studies have demonstrated that MRPL12 is involved in the progression of diabetic kidney disease (DKD) and acute kidney injury (AKI). However, its specific role in ccRCC remains unclear. Therefore, this study aims to elucidate the function of MRPL12 in the metabolic reprogramming of ccRCC.</p><p><strong>Methods: </strong>Online databases and tissue microarray analysis were utilized to explore the role of MRPL12 in ccRCC. Quantitative real-time PCR (qRT-PCR) was performed to quantify mRNA expression levels, while Western blotting, immunofluorescence (IF), and immunohistochemistry (IHC) were employed to evaluate protein expression of the relevant genes. In vitro functional assays were conducted to determine the biological effects of MRPL12, and aerobic glycolysis was assessed using Seahorse XF Analyzers to measure cellular metabolic activity. Mass spectrometry analysis, combined with Gene Ontology (GO) analysis and integrated with Ingenuity Pathway Analysis (IPA), was carried out to identify potential pathway interconnections. To investigate the regulatory mechanism, chromatin immunoprecipitation (ChIP) assays were performed to examine the binding interaction between HIF-1α and the MRPL12 promoter. Finally, an in vivo mouse model was established to further elucidate the functional role of MRPL12 in ccRCC progression.</p><p><strong>Results: </strong>MRPL12 is significantly downregulated in ccRCC tissues, and its reduced expression is associated with poor prognosis. MRPL12 inhibits ccRCC cell proliferation, migration, and invasion by modulating mitochondrial metabolism. Overexpression of MRPL12 enhances oxidative phosphorylation (OXPHOS) and suppresses aerobic glycolysis, while MRPL12 knockdown produces the opposite effects. Potential interconnections between the MRPL12, ILK, ISGylation, and SUMO pathways have been identified. Additionally, HIF-1α was found to act as a transcriptional repressor of MRPL12.</p><p><strong>Conclusion: </strong>Our study reveals that MRPL12 regulates mitochondrial metabolism to inhibit ccRCC cell proliferation, migration, and invasion, suggesting that targeting MRPL12 may represent a promising therapeutic strategy for ccRCC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"435"},"PeriodicalIF":8.2,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145294411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippo pathway suppression reprograms TNFα-primed glioblastoma extracellular vesicles transcripts cargo to drive mesenchymal stem/stromal cells vasculogenic mimicry.","authors":"Rosalie Zilinski, Angélique Sabaoth Konan, Alain Zgheib, Nicoletta Eliopoulos, Luc H Boudreau, Borhane Annabi","doi":"10.1186/s12964-025-02401-x","DOIUrl":"10.1186/s12964-025-02401-x","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) secrete extracellular vesicles (EVs) which play a pivotal role in brain tumor progression by mediating intercellular communication within the inflamed tumor microenvironment (TME). EVs' cargo transports biomolecules that promote tumor progression, immune evasion, and resistance to therapies. While Hippo inhibitors play a significant role in mitigating cancer inflammation, their specific impact on EVs cargo remains unknown.</p><p><strong>Methods: </strong>Human grade IV U87 GBM-derived cells were cultured and EVs isolated from the conditioned media of tumor necrosis factor (TNF)α-primed cells. Total RNA was extracted using TRIzol™, and differential gene expression assessed through gene arrays and validated by RT-qPCR. Protein cell and EVs lysates were used for immunoblotting. 3D mesenchymal stem/stromal cells (MSC) in vitro vasculogenic mimicry (VM) was assessed using Cultrex matrices.</p><p><strong>Results: </strong>Our study shows that U87 cells are responsive to pro-inflammatory stimulation by TNFα as the phosphorylation status of ERK, IκB, and NFκB increased. Among the Hippo pathway inhibitors tested, VT107 inhibited both the TNFα-induced phosphorylation, induction of the downstream Hippo pathway CYR61, and cargo of secreted EVs as assessed upon gene array screens. Pro-inflammatory genes that were reduced by VT107 in EVs included, among others, COX2, IL6, IL1B, and several members of the CCL, CXCL, and Interleukin/Interleukin receptors family. EVs isolated from VT107-treated TNFα-primed U87 cells had decreased paracrine regulation of MSC in vitro VM.</p><p><strong>Conclusions: </strong>By inhibiting the Hippo pathway and TNFα-induced pro-inflammatory cargo of GBM-derived EVs, our data support VT107 as a potential candidate to inhibit tumor-promoting processes involved in therapy resistance such as paracrine induction of MSC-mediated VM.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"434"},"PeriodicalIF":8.2,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145294465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}