Journal of Experimental & Clinical Cancer Research最新文献

{"title":"A novel HVEM-Fc recombinant protein for lung cancer immunotherapy.","authors":"Yuanshan Yao, Bin Li, Jing Wang, Chunji Chen, Wen Gao, Chunguang Li","doi":"10.1186/s13046-025-03324-8","DOIUrl":"https://doi.org/10.1186/s13046-025-03324-8","url":null,"abstract":"<p><strong>Background: </strong>The ubiquitously expressed transmembrane protein, Herpesvirus Entry Mediator (HVEM), functions as a molecular switch, capable of both activating and inhibiting the immune response depending on its interacting ligands. HVEM-Fc is a novel recombinant fusion protein with the potential to eradicate tumor cells.</p><p><strong>Methods: </strong>The anti-tumor efficacy of HVEM-Fc was evaluated in C57BL/6 mice-bearing lung cancer models: a syngeneic model and an orthotopic model of mouse lung cancer. Additionally, patient-derived organoids were employed in conjunction with T cell co-culture systems. To investigate the underlying mechanisms, a comprehensive array of techniques was utilized, including single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and flow cytometry. Furthermore, the anti-tumor effects of HVEM-Fc in combination with Programmed Death-1 (PD-1) inhibitors were assessed. Finally, mouse immune cell depletion antibodies were used to elucidate the underlying mechanisms of action.</p><p><strong>Results: </strong>In vivo, 1 mg/kg HVEM-Fc demonstrated effective inhibition of tumor growth and metastasis in C57BL/6 mice bearing lung cancer model and a KP orthotopic model of mouse lung cancer. Multi-omics analysis showed that HVEM-Fc induced an immune-stimulatory microenvironment. Notably, the combination of HVEM-Fc with a PD-1 inhibitor demonstrated the most potent inhibition of tumor cell growth. In vitro, HVEM-Fc was validated to eradicate tumor cells through the activation of T cells in both non-small cell lung cancer (NSCLC) organoids and T cell co-culture models.</p><p><strong>Conclusions: </strong>Our data demonstrate that HVEM-Fc exerts a strong signal that augments and prolongs T-cell activity in both murine models and human NSCLC organoid models. Moreover, the combination of HVEM-Fc with a PD-1 inhibitor yields the most effective anti-tumor outcomes.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"62"},"PeriodicalIF":11.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDCA3-MYC positive feedback loop promotes bladder cancer progression via ENO1-mediated glycolysis.","authors":"Dexin Shen, Xiang Yu, Xuefeng Fan, Yu Liang, Dongmei Lu, Zongpan Ke, Lei Wang, Ping Xiang, Jun Xiao","doi":"10.1186/s13046-025-03325-7","DOIUrl":"https://doi.org/10.1186/s13046-025-03325-7","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer (BLCA) ranks among the most prevalent malignancies of the urinary system, with its clinical diagnosis predominantly reliant on invasive procedures. Traditional chemotherapy regimens exhibit significant limitations, underscoring the urgency of identifying novel diagnostic biomarkers and strategies to enhance chemotherapy efficacy. CDCA3 has been recognized as a facilitator of BLCA progression, activated by MYBL2. However, its precise regulatory mechanisms in BLCA pathogenesis remain incompletely elucidated.</p><p><strong>Methods: </strong>To investigate the functional role of CDCA3 in BLCA, MTT and colony formation assays were employed to assess cellular proliferation, while flow cytometry was utilized to evaluate apoptosis and intracellular ROS levels. The expression of CDCA3, ENO1, TRIM28, and MYC was analyzed through WB and qRT-PCR, and Co-IP assays were conducted to delineate interactions among CDCA3, TRIM28, and MYC.</p><p><strong>Results: </strong>CDCA3, a key regulator of the cell cycle, facilitates BLCA glycolysis by modulating the transcriptional expression of α-Enolase (ENO1), thereby enhancing BLCA progression. Mechanistically, CDCA3 recruits TRIM28, which stabilizes MYC, while MYC transcriptionally upregulates CDCA3, establishing a self-reinforcing CDCA3-MYC feedback loop. A risk prediction model incorporating the expression profiles of CDCA3 and ENO1 was developed to evaluate the overall survival of patients with BLCA. This model provides a prognostic tool to predict survival outcomes in patients with BLCA based on CDCA3 and ENO1 expression levels.</p><p><strong>Conclusions: </strong>This study delineates a novel role for CDCA3 in the regulation of BLCA glycolysis and identifies its interaction with MYC as a critical positive feedback mechanism, providing fresh insights into the molecular mechanisms underlying BLCA progression.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"63"},"PeriodicalIF":11.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MMP28 recruits M2-type tumor-associated macrophages through MAPK/JNK signaling pathway-dependent cytokine secretion to promote the malignant progression of pancreatic cancer.","authors":"Shi Dong, Xin Li, Zhou Chen, Huaqing Shi, Zhengfeng Wang, Wence Zhou","doi":"10.1186/s13046-025-03321-x","DOIUrl":"https://doi.org/10.1186/s13046-025-03321-x","url":null,"abstract":"<p><strong>Background: </strong>Crosstalk between pancreatic cancer cells and tumor-associated macrophages (TAMs) is a critical driver of malignant progression, and plays an important role in the low response rate to immunotherapy in patients with for pancreatic cancer. Although it is known that cancer cells induce TAM infiltration and M2 polarization, the underlying mechanisms remain elusive. Herein, we identified matrix metalloproteinase 28 (MMP28), a highly expressed protein, as a key regulator of this process.</p><p><strong>Methods: </strong>Immunohistochemical staining and qRT-PCR were used to validate MMP28 as a potential marker for the prognosis of patients with pancreatic cancer. We evaluated the tumor-promoting effect of MMP28 in vitro with CCK-8, Transwell, and EdU assay and Western blotting and explored the potential mechanism of MMP28-induced M2 polarization of TAMs with a coculture system, immunofluorescence staining and flow cytometry. A subcutaneous graft tumor model was constructed to assess the tumor-promoting effect of MMP28 and its ability to induce M2 TAM infiltration.</p><p><strong>Results: </strong>The relevant results of this study revealed a strong correlation between MMP28 expression and TAM infiltration, with a predominance of M2-polarized TAMs in pancreatic cancer tissues. Mechanistic investigations demonstrated that MMP28 promotes the secretion of multiple cytokines, including IL-8 and VEGFA through the activation of the MAPK/JNK signaling pathway. These cytokines act as potent chemoattractants and polarizing factors for TAMs. Additionally, we discovered an interaction between MMP28 and ANXA2, which contributes to the regulation of TAM recruitment and polarization. In vivo studies confirmed the critical role of MMP28 in tumor growth and TAM infiltration. Depletion of macrophages, inhibition of JNK, or neutralization of IL-8 and VEGFA significantly suppressed tumor progression. Transcriptomic analysis suggested that IL-8 and VEGFA induce M2 TAM polarization by modulating TAM amino acid metabolism.</p><p><strong>Conclusions: </strong>Collectively, our findings elucidate a novel mechanism by which pancreatic cancer cells manipulate the tumor microenvironment through MMP28-dependent cytokine secretion, promoting TAM infiltration and M2 polarization. These results highlight MMP28 as a promising therapeutic target for pancreatic cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"60"},"PeriodicalIF":11.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABA regulates metabolic reprogramming to mediate the development of brain metastasis in non-small cell lung cancer.","authors":"Mengqing Xie, Hao Qin, Li Liu, Jing Wu, Zhikai Zhao, Yaodong Zhao, Yujia Fang, Xin Yu, Chunxia Su","doi":"10.1186/s13046-025-03315-9","DOIUrl":"https://doi.org/10.1186/s13046-025-03315-9","url":null,"abstract":"<p><strong>Background: </strong>Brain metastasis (BrM) poses a significant challenge to the prognosis and quality of life for patients with non-small cell lung cancer (NSCLC). Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system (CNS), has been implicated in the progression of various tumors. However, its potential role in BrM of NSCLC and the underlying mechanisms remain largely unexplored.</p><p><strong>Methods: </strong>A multi-omics approach combined with in vivo and in vitro experiments identified GABA as a key target in BrM of NSCLC. Functional and mechanistic studies were conducted to investigate how GABA mediates brain metastasis through the activation of the NF-κB pathway.</p><p><strong>Results: </strong>GABA levels were significantly elevated in both cells and serum of patients with NSCLC who had BrM. GABA markedly enhanced the brain metastatic capabilities and malignancy of NSCLC cells. Mechanistically, tumor cells with a tendency for brain metastasis can inhibit 4-aminobutyrate aminotransferase (ABAT) by downregulating forkhead box A2 (FOXA2) expression, leading to increased GABA accumulation. GABA subsequently activates the NF-κB pathway and the astrocytes, thus facilitating the brain metastasis of NSCLC.</p><p><strong>Conclusions: </strong>Our findings indicate that GABA plays a crucial role in the development of NSCLC brain metastasis by activating the NF-κB pathway through the FOXA2/ABAT/GABA axis. Additionally, the interaction between NSCLC and astrocytes creates an inhibitory microenvironment that promotes tumor colonization.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"61"},"PeriodicalIF":11.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highlighting recent achievements to advance more effective cancer immunotherapy.","authors":"Beatrice Belmonte, Sheila Spada, Paola Allavena, Matteo Benelli, Vincenzo Bronte, Giulia Casorati, Lorenzo D'Ambrosio, Roberto Ferrara, Anna Mondino, Paola Nisticò, Roberta Sommaggio, Marcella Tazzari, Claudio Tripodo, Antonio Sica, Pier Francesco Ferrucci","doi":"10.1186/s13046-025-03316-8","DOIUrl":"10.1186/s13046-025-03316-8","url":null,"abstract":"<p><p>From 17 to 19th October 2024, the XXI Italian Network for Bio-Immunotherapy of Tumors Meeting (NIBIT) took place in Palermo, in the marvelous historical location of Teatro Politeama, under the auspices of the Italian Association of Medical Oncology (AIOM), Italian Association of Cancer Research (AIRC), Fondazione Pezcoller, Italian Alliance against Cancer (ACC), Italian Lymphoma Foundation (FIL), Grazia Focacci Foundation and Melagioco Foundation. The conference covered a spectrum of topics ranging from target discovery to therapeutic advances in immuno-oncology, bringing world-renowned experts to present groundbreaking innovations in basic, translational, and clinical cancer research. Six sessions focused on cellular therapies, digital pathology, vaccines, tertiary lymphoid structures, and microenvironment in order to get deep insights on how to personalize diagnosis and therapies in the clinical setting. Young investigators had the opportunity to meet and greet their mentors, promoting the synergy of the academic and industrial sectors within the national and international panorama, discussing the application of artificial intelligence on multi-specific antibodies, drug conjugates, and antibody fusion proteins that are advancing the efficacy of precision medicine and minimizing off-target effects.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"57"},"PeriodicalIF":11.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: N⁶ -methyladenosine modification of circMARK2 enhances cytoplasmic export and stabilizes LIN28B, contributing to the progression of Wilms tumor.","authors":"Guannan Shu, Zhang Zhao, Tianxin Zhao, Changmi Deng, Jiangquan Zhu, Yufeng Han, Minyu Chen, Jiajia Jing, Gaochen Bai, Dian Li, Feng Li, Jing He, Wen Fu, Guochang Liu","doi":"10.1186/s13046-025-03326-6","DOIUrl":"10.1186/s13046-025-03326-6","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"59"},"PeriodicalIF":11.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implication for precision epigenetic therapy.","authors":"Maria Fortunata Lofiego, Rossella Tufano, Emma Bello, Laura Solmonese, Francesco Marzani, Francesca Piazzini, Fabrizio Celesti, Francesca Pia Caruso, Teresa Maria Rosaria Noviello, Roberta Mortarini, Andrea Anichini, Michele Ceccarelli, Luana Calabrò, Michele Maio, Sandra Coral, Anna Maria Di Giacomo, Alessia Covre","doi":"10.1186/s13046-025-03310-0","DOIUrl":"https://doi.org/10.1186/s13046-025-03310-0","url":null,"abstract":"<p><strong>Background: </strong>Co-targeting of immune checkpoint inhibitors (ICI) CTLA-4 and PD-1 has recently become the new first-line standard of care therapy of pleural mesothelioma (PM) patients, with a significant improvement of overall survival (OS) over conventional chemotherapy. The analysis by tumor histotype demonstrated greater efficacy of ICI therapy compared to standard chemotherapy in non-epithelioid (non-E) vs. epithelioid (E) PM, although some E PM patients also benefit from ICI treatment. This evidence suggests that molecular tumor features, beyond histotype, could be relevant to improve the efficacy of ICI therapy in PM. Among these, tumor DNA methylation emerges as a promising factor to explore, due to its potential role in driving the immune phenotype of cancer cells. Therefore, we utilized a panel of cultured PM cells of different histotype to provide preclinical evidence supporting the role of the tumor methylation landscape, along with its pharmacologic modulation, to prospectively improve the efficacy of ICI therapy of PM patients.</p><p><strong>Methods: </strong>The methylome profile (EPIC array) of distinct E (n = 5) and non-E (n = 9) PM cell lines was analyzed, followed by integrated analysis with their associated transcriptomic profile (Clariom S array), before and after in vitro treatment with the DNA hypomethylating agent (DHA) guadecitabine. The most variable methylated probes were selected to calculate the methylation score (CIMP index) for each cell line at baseline. Genes that were differentially expressed (DE) and differentially methylated (DM) were then selected for gene ontology analysis.</p><p><strong>Results: </strong>The CIMP index stratified PM cell lines into two distinct classes, CIMP (hyper-methylated; n = 7) and LOW (hypo-methylated; n = 7), regardless of their E or non-E histotype. Integrated methylome and transcriptome analyses revealed that CIMP PM cells exhibited a substantial number of hyper-methylated, silenced genes, which negatively impacted their immune phenotype compared to LOW PM cells. Treatment with DHA reverted the methylation-driven immune-compromised profile of CIMP PM cells and enhanced the constitutive immune-favorable profile of LOW PM cells.</p><p><strong>Conclusion: </strong>The study highlighted the relevance of DNA methylation in shaping the constitutive immune classification of PM cells, independent of their histological subtypes. The identified role of DHA in shifting the phenotype of PM cells towards an immune-favorable state highlights its potential for evaluation in phase I/II clinical trials investigating the efficacy of epigenetic-based ICI combinations to reverse cancer immune resistance mechanisms.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"58"},"PeriodicalIF":11.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting TUBB2B inhibits triple-negative breast cancer growth and brain-metastatic colonization.","authors":"Qingling He, Jianyang Hu, Fung-Yin Ngo, Huiqi Zhang, Lin He, Hao Huang, Tan Wu, Yilin Pan, Zihan Yang, Yuanyuan Jiang, William C Cho, Wah Cheuk, Gary M Tse, Julia Y Tsang, Mengsu Yang, Liang Zhang, Xin Wang, Pui-Chi Lo, C Geoffrey Lau, Y Rebecca Chin","doi":"10.1186/s13046-025-03312-y","DOIUrl":"10.1186/s13046-025-03312-y","url":null,"abstract":"<p><strong>Background: </strong>The triple-negative subtype of breast cancer is particularly challenging to treat due to its aggressiveness with a high risk of brain metastasis, and the lack of effective targeted therapies. Tubulin beta 2B class IIb (TUBB2B), a β-tubulin isoform regulating axon guidance during embryonic development, was found to be overexpressed in various types of cancers including triple-negative breast cancer (TNBC). However, its functional roles in breast cancer or metastasis remain unclear.</p><p><strong>Methods: </strong>To identify TUBB2B as a novel molecular target in TNBC, we performed bioinformatics analysis to assess the association of TUBB2B expression and survival of patients. RNAscope in situ hybridization was used to examine TUBB2B expression in clinical breast tumor samples. The effect of TUBB2B knockdown on TNBC growth and brain metastasis colonization was evaluated by in vitro and in vivo assays. Mass spectrometry (MS) and biochemical experiments were performed to explore the underlying mechanisms. Preclinical efficacy of targeting TUBB2B was determined in xenograft studies using the siRNA-gold nanoparticle (siRNA-AuNP) approach.</p><p><strong>Results: </strong>TUBB2B, but not other β-tubulin isoforms, is frequently overexpressed in TNBC primary tumors as well as brain metastases. We also find that upregulation of TUBB2B is associated with poor prognosis in breast cancer patients. Silencing TUBB2B induces tumor cell death and inhibits the outgrowth of brain metastasis. Mechanistically, we identify eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) as a novel interacting partner of TUBB2B, revealing a previously unexplored role of TUBB2B in translational regulation. In line with its neural-related functions, TUBB2B overexpression in TNBC cells activates astrocytes, which in turn upregulate TUBB2B in tumor cells. These findings suggest a feed-forward interaction between TUBB2B in TNBC cells and astrocytes that promotes brain metastatic colonization. Furthermore, we demonstrate the potent inhibition of TNBC xenograft growth as well as brain metastatic colonization using TUBB2B siRNA-AuNP treatment, indicating potential clinical applications of targeting TUBB2B for TNBC.</p><p><strong>Conclusions: </strong>TUBB2B is a novel TNBC gene that plays a key role in promoting tumor cell survival and brain metastatic colonization, and can be targeted by siRNA-AuNPs as a treatment strategy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"55"},"PeriodicalIF":11.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AZIN1 level is increased in medulloblastoma and correlates with c-Myc activity and tumor phenotype.","authors":"Julie Sesen, Tyra Martinez, Sara Busatto, Larysa Poluben, Hassan Nassour, Caroline Stone, Karthik Ashok, Marsha A Moses, Edward R Smith, Aram Ghalali","doi":"10.1186/s13046-025-03274-1","DOIUrl":"10.1186/s13046-025-03274-1","url":null,"abstract":"<p><strong>Background: </strong>AZIN1 is a cell cycle regulator that is upregulated in a variety of cancers. AZIN1 overexpression can induce a more aggressive tumor phenotype via increased binding and resultant inhibition of antizyme. Antizyme is a protein that normally functions as an anti-tumor regulator that facilitates the deactivation of several growth-promoting proteins including c-Myc. MYC plays a critical role in medulloblastoma pathogenesis. Its amplification serves as a defining characteristic of group 3 medulloblastomas, associated with the most aggressive clinical course, greater frequency of metastases, and shorter survival times.</p><p><strong>Methods: </strong>Medulloblastoma tissues (68 TMA, and 45 fresh tissues, and 31 controls) were stained (fluorescence and immunohistochemical) for AZIN1. Western blotting and ELISA were used to detect the AZIN1 level. Phenotypically aggressive cellular features were measured by increased invasion, colony formation and proliferation. CRISPR-Cas9-mediated AZIN1 knocked-out cells were orthotopically implanted in the cerebellum of nude mice (n = 8/group) with a stereotactic frame. Tumor growth was monitored using the In Vivo Imaging System (IVIS).</p><p><strong>Results: </strong>Here, we investigated the role of AZIN1 expression in medulloblastoma. We found that overexpression of AZIN1 in medulloblastoma cells induces phenotypically aggressive features. Conducting in vivo studies we found that knocking-out AZIN1 in tumors corresponds with reduced tumor progression and prolonged survival. Clinical specimens are revealing that AZIN1 is highly expressed and directly correlates with MYC amplification status in patients.</p><p><strong>Conclusion: </strong>These data implicate AZIN1 as a putative regulator of medulloblastoma pathogenesis and suggest that it may have clinical application as both a biomarker and novel therapeutic target.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"56"},"PeriodicalIF":11.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of Spry1 reduces HIF1α-dependent glycolysis and impairs angiogenesis in BRAF-mutant cutaneous melanoma.","authors":"Barbara Montico, Giorgio Giurato, Roberto Guerrieri, Francesca Colizzi, Annamaria Salvati, Giovanni Nassa, Jessica Lamberti, Domenico Memoli, Patrizia Sabatelli, Marina Comelli, Arianna Bellazzo, Albina Fejza, Lucrezia Camicia, Lorena Baboci, Michele Dal Bo, Alessia Covre, Tuula A Nyman, Alessandro Weisz, Agostino Steffan, Michele Maio, Luca Sigalotti, Maurizio Mongiat, Eva Andreuzzi, Elisabetta Fratta","doi":"10.1186/s13046-025-03289-8","DOIUrl":"10.1186/s13046-025-03289-8","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;About 50% of cutaneous melanoma (CM) harbors the activating BRAF&lt;sup&gt;V600&lt;/sup&gt; mutation which exerts most of the oncogenic effects through the MAPK signaling pathway. In the last years, a number of MAPK modulators have been identified, including Spry1. In this context, we have recently demonstrated that knockout of Spry1 (Spry1&lt;sup&gt;KO&lt;/sup&gt;) in BRAF&lt;sup&gt;V600&lt;/sup&gt;-mutant CM led to cell cycle arrest and apoptosis, repressed cell proliferation in vitro, and reduced tumor growth in vivo. Despite these findings, however, the precise molecular mechanism linking Spry1 to BRAF&lt;sup&gt;V600&lt;/sup&gt;-mutant CM remains to be elucidated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Materials and methods: &lt;/strong&gt;Immunoprecipitation coupled to mass spectrometry was employed to gain insight into Spry1 interactome. Spry1 gene was knocked-out using the CRISPR strategy in the BRAF-mutant cell lines. Transmission electron microscopy was used to assess the relationship between Spry1 expression and mitochondrial morphology. By using in vitro and in vivo models, the effects of Spry1&lt;sup&gt;KO&lt;/sup&gt; were investigated through RNA-sequencing, quantitative real-time PCR, Western blot, and immunofluorescence analyses. The Seahorse XF24 assay allowed real-time measurement of cellular metabolism in our model. Angiogenic potential was assessed through in vitro tube formation assays and in vivo CD31 staining.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Spry1 was mainly located in mitochondria in BRAF&lt;sup&gt;V600&lt;/sup&gt;-mutant CM cells where it interacted with key molecules involved in mitochondrial homeostasis. Spry1 loss resulted in mitochondrial shape alterations and dysfunction, which associated with increased reactive oxygen species production. In agreement, we found that nuclear hypoxia-inducible factor-1 alpha (HIF1α) protein levels were reduced in Spry1&lt;sup&gt;KO&lt;/sup&gt; clones both in vitro and in vivo along with the expression of its glycolysis related genes. Accordingly, Ingenuity Pathway Analysis identified \"HIF1α Signaling\" as the most significant molecular and cellular function affected by Spry1 silencing, whereas the glycolytic function was significantly impaired in Spry1 depleted BRAF&lt;sup&gt;V600&lt;/sup&gt;-mutant CM cells. In addition, our results indicated that the expression of the vascular endothelial growth factor A was down-regulated following Spry1&lt;sup&gt;KO&lt;/sup&gt;, possibly as a result of mitochondrial dysfunction. Consistently, we observed a substantial impairment of angiogenesis, as assessed by the tube formation assay in vitro and the immunofluorescence staining of CD31 in vivo.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Altogether, these findings identify Spry1 as a potential regulator of mitochondrial homeostasis, and uncover a previously unrecognized role for Spry1 in regulating nuclear HIF1α expression and angiogenesis in BRAF&lt;sup&gt;V600&lt;/sup&gt;-mutant CM.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Significance: &lt;/strong&gt;Spry1&lt;sup&gt;KO&lt;/sup&gt; profoundly impacts on mitochondria homeostasis, while concomitantly impairing HIF1α-d","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"53"},"PeriodicalIF":11.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}