Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Reciprocal regulation of MMP-28 and EGFR is required for sustaining proliferative signaling in PDAC.","authors":"Zhengtao Hong, Xing Huang, Linghao Xia, Tingbo Liang, Xueli Bai","doi":"10.1186/s13046-025-03323-9","DOIUrl":"10.1186/s13046-025-03323-9","url":null,"abstract":"<p><strong>Backgroud: </strong>Sustaining proliferation signaling is the top hallmarks of cancer, driving continuous tumor growth and resistance to drug treatments. Blocking proliferation signaling has shown limited benefit in clinical treatment of pancreatic ductal adenocarcinoma, highlighting the urgent need to deeply understand proliferation signaling and develop new therapeutic strategies.</p><p><strong>Methods: </strong>By leveraging clinical data and data from the TCGA and GDSC datasets, we investigated the association between MMP-28 expression and the sensitivity to EGFR inhibitors as well as the prognosis of PDAC. Transcriptomic and biological experiments explore the regulatory role of MMP-28 on the EGFR signaling pathway. Additionally, in vitro and in vivo studies are employed to evaluate MMP-28 as a biomarker for sensitivity to EGFR inhibitors.</p><p><strong>Results: </strong>We found that MMP-28, a metalloproteinase, was significantly associated with the sensitivity to EGFR inhibitors. Furthermore, MMP-28 could promote PDAC growth and metastasis. Mechanistically, MMP-28 facilitated the maturation and release of the TGF-α precursor, thus promoting EGFR activation. In return, EGFR upregulated MMP-28 through AP-1-mediated transcription, forming a positive feedback loop that provided sustaining proliferation signaling for PDAC. Subsequently, MMP-28 was identified to predict the response to EGFR inhibitors and recognize responsive patients.</p><p><strong>Conclusions: </strong>Our findings revealed the role of MMP-28 and EGFR in generation of sustaining proliferation signaling and provided a new therapy strategy for PDAC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"68"},"PeriodicalIF":11.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143494343","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":"Correction: Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion.","authors":"Juan Li, Jie Liu, Pingping Li, Xiaona Mao, Wenjie Li, Jin Yang, Peijun Liu","doi":"10.1186/s13046-025-03317-7","DOIUrl":"10.1186/s13046-025-03317-7","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"66"},"PeriodicalIF":11.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484576","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":"CD47 blockade reverses resistance to HDAC inhibitor by liberating anti-tumor capacity of macrophages.","authors":"Xutao Xu, Qianqian Wang, Ke Guo, Junjie Xu, Yunkun Lu, Huijuan Chen, Weilin Hu, Yilin Fu, Lu Sun, Ying He, Zhehang Chen, Wenhao Xia, Mengtian Pan, Beibei Lin, Wenjuan Yang, Qingqing Wang, Zhenzhen Wen, Qian Cao, Peng Xiao","doi":"10.1186/s13046-025-03335-5","DOIUrl":"10.1186/s13046-025-03335-5","url":null,"abstract":"<p><strong>Background: </strong>Targeting oncogenic histone modification by histone deacetylase inhibitors (HDACis) demonstrates promising prospects in clinical cancer treatment, whereas a notable proportion of patients cannot benefit from HDACi therapy. This study aims to explore how HDACi influences the tumor microenvironment, in order to identify potential targets for reversing the resistance to HDACi therapies.</p><p><strong>Methods: </strong>Macrophage infiltration was compared between HDACi-responding and HDACi-nonresponding cancer patients. The impact of HDACis on the phagocytic capacity of macrophages was investigated through macrophage-tumor cell co-culture system. CD47 expression in tumor cell lines and patient-derived organoids was evaluated by quantitative polymerase chain reaction (QPCR) and flow cytometry. Mechanistic studies were conducted through co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP). The synergistic effect of HDACis and CD47 neutralizing antibody was assessed in subcutaneous murine tumor models. Bioinformatics approaches were adopted to analyze how macrophage infiltration determines the prognostic significance of CD47 expression in cancer patients.</p><p><strong>Results: </strong>High macrophage infiltration is a determinant of therapeutic non-response to HDACi, cancer patients who did not respond to HDACi exhibit massive infiltration of tumor-associated macrophages (TAMs). TAM depletion reversed the resistance to HDACi therapy. Mechanistically, HDACi impaired the phagocytic capacity of macrophages against tumor cells through epigenetically upregulating CD47 expression. Reciprocally, HDACi-upregulated CD47 polarized macrophages towards a pro-tumor M2 phenotype through SIRPα ligation. In tumor-bearing mice, HDACi monotherapy only marginally delayed tumor progression, while the concurrent neutralization of CD47 exhibited potent anti-tumor effect through re-educating TAMs towards a tumoricidal phenotype. In cancer patients, CD47 was found to determine the prognostic significance of TAMs.</p><p><strong>Conclusions: </strong>Our study offers a rationale for targeting macrophage infiltration or blocking CD47 to sensitize HDACi therapies in cancer patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"67"},"PeriodicalIF":11.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143494341","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":"miRNA-503 inhibition exerts anticancer effects and reduces tumor growth in mesothelioma.","authors":"Miriam Piccioni, Francesco Di Meo, Anna Valentino, Virginia Campani, Maddalena Arigoni, Mirella Tanori, Mariateresa Mancuso, Rossana Cuciniello, Marco Tomasetti, Federica Monaco, Gaia Goteri, Enrico P Spugnini, Raffaele A Calogero, Giuseppe De Rosa, Gianfranco Peluso, Alfonso Baldi, Stefania Crispi","doi":"10.1186/s13046-025-03283-0","DOIUrl":"10.1186/s13046-025-03283-0","url":null,"abstract":"<p><strong>Background: </strong>Malignant mesothelioma (MM) is a rare and aggressive form of cancer that affects the mesothelial surfaces, associated with exposure to asbestos fibres. To date, no cure is available for MM and therapeutically approved treatments are based on the use of platinum compounds often used in combination with other drugs. We have previously analysed the efficacy of a cisplatin/piroxicam (CDDP/P) combined treatment showing that this treatment was able to reduce in vivo tumor growth. Several studies reported that platinum-drug sensitivity in cancer is connected to modulation of the expression of non-coding RNAs. In this study we analysed if the CDDP/P treatment was able to modulate miRNAs expression in MM.</p><p><strong>Methods: </strong>miRNA sequencing performed on MSTO-211 H cells treated with CDDP with CDDP/P led us to identify miRNA-503 - downregulated by CDDP/P - as a novel miRNA that acts as an oncomiR in MM. The effect of miRNA-503 inhibition was evaluated in vitro in mesothelioma cells analysing apoptosis induction and reduction of cancer properties. Inhibition of miR-503 expression in vivo, was analysed in ectopic mouse model of MM by using LNP encapsulating anti-mir-503 and miR-503 expression was evaluated in human MM samples.</p><p><strong>Results: </strong>In vitro and in vivo analysis confirmed miR-503 acts as oncogene in MM since its inhibition was able to reduce cell cancer properties and tumor growth in ectopic mouse model of MM. Its expression was found upregulated in human MM patients compared to normal pleura. Bioinformatic analysis indicated BTG1, CCNG1, EDG1, and TIMP2 as putative target genes of miRNA-503. These genes showed an opposite expression compared to miR-503 levels both in cells and in MM samples. Finally, microarray analysis indicated that miR-503 inhibition affected the expression of the well-known MM biomarkers: CXCL8, SERPINE1 and Osteopontin.</p><p><strong>Conclusions: </strong>Our study is the first reporting an oncomiR role for miR-503 in MM and suggests that its inactivation could have a clinical value in MM patients. This study reveals that miRNA-503 acts as an oncomiR in MM suggesting that its inhibition, through LNP delivery, has the potential to be considered as a novel therapeutic strategy in MM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"65"},"PeriodicalIF":11.4,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473157","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":"The extracellular matrix protein type I collagen and fibronectin are regulated by β-arrestin-1/endothelin axis in human ovarian fibroblasts.","authors":"Ilenia Masi, Flavia Ottavi, Valentina Caprara, Danila Del Rio, Martina Kunkl, Francesca Spadaro, Valerio Licursi, Loretta Tuosto, Anna Bagnato, Laura Rosano'","doi":"10.1186/s13046-025-03327-5","DOIUrl":"10.1186/s13046-025-03327-5","url":null,"abstract":"<p><strong>Background: </strong>The invasive and metastatic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and stroma, which include extracellular matrix (ECM) and cellular components, including cancer-associated fibroblasts (CAFs). Soluble factors secreted by cancer and stromal cells contribute to stroma remodeling through the secretion of ECM proteins, providing a favorable environment for cancer cell dissemination. The peptide endothelin-1 (ET-1), through two G protein-coupled receptors (GPCR), endothelin receptor type A (ET_AR) and B (ET_BR), acts on both cancer and stromal cells, engaging the protein β-arrestin1 (β-arr1), to bolster SOC progression. However, its role in the regulation of the ECM proteins by ovarian fibroblasts is not understood. This study delves into the role of ET-1 as a regulator of type I collagen (Col1) and fibronectin (FN).</p><p><strong>Methods: </strong>We used human primary ovarian fibroblasts (HOFs) and CAFs. The expression of Col1 (COL1A1) and FN (FN1) were detected by western blotting (WB), quantitative real time-polymerase chain reaction (qRT-PCR), immunofluorescence (IF), and confocal laser scanning microscopy (CLSM) in cells and tumor tissue sections from mice xenografts, while the transcription of COL1A1 was detected by luciferase reporter gene assay. The nuclear function of β-arr1 was evaluated by silencing and rescue expression with wild-type (WT) and nuclear mutant plasmid constructs, RNA seq and differential gene expression and gene sets enrichment analyses. The prognostic role of COL1A1, FN1, EDN1 (ET-1) and ARRB1 (β-arr1) gene expression was evaluated using the Kaplan-Meier plotter database and clinical ovarian cancer tissue samples.</p><p><strong>Results: </strong>We demonstrated that ET-1 boosts Col1 and FN expression in HOFs, akin to ovarian CAF levels. Both receptors are implicated, evident from inhibitory effects after ET_AR or ET_BR antagonist treatments and notably with bosentan, a dual antagonist, in vitro and in vivo. At the molecular level, ET-1 triggers the activation of COL1A1 promoter activity and its enhanced expression via β-arr1 nuclear function. Transcriptome analysis of β-arr1-silenced HOFs confirms the nuclear role of β-arr1 in collagen and ECM remodeling-related protein transcriptional regulation. Accordingly, a high level of EDN1/ARRB1 expression in combination with either COL1A1 or FN1 is associated with the poor prognosis of SOC patients.</p><p><strong>Conclusions: </strong>These findings hint at ET-1 involvement in ECM remodeling and early SOC stages by modulating the expression of Col1 and FN. Targeting ET-1 signaling with ET_AR/ET_BR antagonists might interfere with the ability of CAFs to produce key ECM proteins in this tumor.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"64"},"PeriodicalIF":11.4,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473160","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":"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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841141/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841255/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837641/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837350/pdf/","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":"OA","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}