Journal of Experimental & Clinical Cancer Research最新文献

{"title":"B7-H3 and CSPG4-targeted CAR T cells as potent effectors in anaplastic thyroid cancer.","authors":"Giulia Cattaneo, Marco Ventin, Shahrzad Arya, Cedric Bailey, Venkata Rao Vantaku, Jingyu Jia, Maoyang Qi, Luke Maggs, Xinhui Wang, Sareh Parangi, Soldano Ferrone, Cristina R Ferrone","doi":"10.1186/s13046-025-03475-8","DOIUrl":"https://doi.org/10.1186/s13046-025-03475-8","url":null,"abstract":"<p><strong>Background: </strong>Anaplastic thyroid cancer (ATC) is a rare and aggressive malignancy with poor survival and no available effective therapy. This unmet clinical need led us to investigate chimeric antigen receptor (CAR) T cells s as potential treatment option for this malignant disease. As target tumor antigens of our CAR T cell therapy, we selected the chondroitin sulfate proteoglycan 4 (CSPG4) and the B7-homolog 3 (B7-H3), as they are both highly and homogeneously expressed on different types of thyroid carcinoma cell lines and tissues, including ATC. Importantly, both CSPG4 and B7-H3 have a low distribution on normal tissues, thus limiting 'on-target off-tumor' CAR T-related toxicities.</p><p><strong>Methods: </strong>We generated CSPG4-specific and B7-H3-specific CAR T cells by utilizing a second-generation CAR construct comprised of a CD28 costimulatory domain and tested their antitumor activity in vitro and in an orthotopic xenograft murine model of ATC.</p><p><strong>Results: </strong>We demonstrated that thyroid cancer cells are specifically recognized and effectively eradicated in vitro by CSPG4-targeted and B7-H3-targeted CAR T cells. Additionally, both CAR T cell types were able to mediate significant control or complete eradication of primary ATC tumors when mice were treated with CSPG4 CAR T cells or B7-H3 CAR T cells, respectively.</p><p><strong>Conclusion: </strong>Overall, in this study we identified CSPG4 and B7-H3 as valuable target antigens in thyroid cancer and demonstrated that CAR T cell immunotherapy can be a valuable therapeutic option for ATC patients. Our findings provide the translational basis for exploring CAR T cell immunotherapies targeting CSPG4 and B7-H3 with ATC patients who do not respond or relapse after first line treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"248"},"PeriodicalIF":12.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977061","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":"Proteomic profiling identifies a stromal TGF-β1/podoplanin axis as a driver of colorectal cancer progression.","authors":"Silvia Di Agostino, Davide La Padula, Vittoria Rago, Caterina Gabriele, Francesco Conforti, Elio Aprigliano, Lidia Urlandini, Elvira Parrotta, Danilo Lofaro, Francesca Vescio, Andrea Sacconi, Valeria Cernaro, Giuseppe Currò, Angela Alibrandi, Girolamo Ranieri, Valeria Zuccalà, Antonio Ieni, Marco Gaspari, Giovanni Cuda, Michele Ammendola, Vittorio Abbonante","doi":"10.1186/s13046-025-03496-3","DOIUrl":"https://doi.org/10.1186/s13046-025-03496-3","url":null,"abstract":"<p><strong>Background: </strong>The tumor microenvironment (TME) plays a pivotal role in the development and progression of colorectal cancer (CRC), yet the complex crosstalk among its components remains incompletely understood. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) have emerged as key regulators of CRC progression, but their specific contributions, particularly given their heterogeneity, are not fully elucidated. This study identifies podoplanin (PDPN), a transmembrane glycoprotein enriched in CAFs, as highly expressed in the CRC TME, in particular surrounding the tumor, and associated with macrophage infiltration and cancer progression.</p><p><strong>Methods: </strong>We performed mass spectrometry-based proteomic analysis on matched CRC and adjacent normal tissues from patients to identify altered signaling pathways and protein expression. The clinical relevance of PDPN expression was evaluated in CRC samples from two independent cohorts using immunohistochemistry and immunofluorescence analysis. Publicly available data from the Gene Expression Omnibus (GEO) database were analyzed to assess the association between PDPN expression and patient survival. Functional assays using direct and indirect co-culture systems investigated the influence of macrophage infiltration on stromal PDPN expression and its effect on colon adenocarcinoma cell growth.</p><p><strong>Results: </strong>PDPN expression was significantly elevated in the stroma of the colorectal tumor tissues compared to normal tissues and correlated with M2-like macrophage infiltration. High PDPN expression was associated with reduced relapse-free survival in CRC patients. Stromal cells pre-conditioned with M2-like macrophages upregulated PDPN and more effectively supported the growth of three colon adenocarcinoma cell lines. PDPN depletion impaired the ability of stromal cells to promote tumor cell proliferation. Mechanistically, M2-like macrophage pre-conditioning induced a TGF-β1-dependent increase in YAP/TAZ nuclear localization, RhoA/ROCK/myosin-driven cytoskeletal contractility, and extracellular matrix (ECM) production in stromal cells. Inhibition of TGF-β1 signaling or ROCK activity reduced stromal support for cancer cell growth.</p><p><strong>Conclusion: </strong>This study reveals a novel mechanism by which the TME facilitates CRC progression and highlights PDPN as a potential prognostic biomarker and therapeutic target in CRC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"247"},"PeriodicalIF":12.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977311","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":"Targeting the interplay of cGAS-STING and ferroptosis by nanomedicine in the treatment of cancer.","authors":"Chunfei Li, Wenyan Zhao, Donghua Geng, Yuzi Jin, Wenzheng Guan","doi":"10.1186/s13046-025-03520-6","DOIUrl":"https://doi.org/10.1186/s13046-025-03520-6","url":null,"abstract":"<p><p>The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway senses cytosolic DNA and triggers innate immune responses. Pharmacological activation of the cGAS-STING pathway by cGAS-STING agonists to overcome cancer drug resistance offers substantial potential to promote antitumor immunity. However, small-molecule STING agonists show rapid excretion, low bioavailability, non-specificity, and adverse effects, which limit their therapeutic efficacy and in vivo applications. The recent emergence of nanomedicine has profoundly revolutionized STING agonist delivery, promoting tumor-targeted delivery and offering new opportunities for tumor-specific immunotherapy. A growing body of evidence has shown that cGAS-STING interacts with ferroptosis in cancer cells. Targeting the interplay between cGAS-STING and ferroptosis using nanomedicines offers a novel cancer treatment regimen. In this review, we outline the principal components of the cGAS-STING signaling cascade and discuss its role in cancer biology. We also review the role of the interplay between cGAS-STING and ferroptosis in cancer genesis. We then focus on providing an overview of the latest findings and emerging concepts that leverage the interplay between cGAS-STING and ferroptosis by nanomedicine to kill cancers. Finally, we discuss the key limitations of the current therapeutic paradigm and possible strategies to overcome them. This article highlights some promising therapeutic avenues that leverage the interplay of cGAS-STING and ferroptosis by nanomedicine, which could be used to treat cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"249"},"PeriodicalIF":12.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144976139","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 new era in cancer therapy: targeting the Proteasome-Bcl-2 axis.","authors":"Sourabh Soni, Vandana Anang, Yutong Zhao, Jeffrey C Horowitz, Richard S Nho, Yohannes A Mebratu","doi":"10.1186/s13046-025-03505-5","DOIUrl":"https://doi.org/10.1186/s13046-025-03505-5","url":null,"abstract":"<p><p>The B-cell lymphoma-2 (Bcl-2) family proteins, key regulators of apoptosis, are frequently dysregulated in cancer, tipping the balance of cell survival and apoptosis in favor of survival. The ubiquitin-proteasome system (UPS) is a critical cellular machinery that controls the Bcl-2 levels through regulation of protein stability. This review delves into the intricate interplay between the proteasome and Bcl-2 family members, exploring how proteasome-mediated degradation impacts cell survival and proliferation to influence cancer progression. We discuss the therapeutic potential of targeting the proteasome-Bcl-2 axis, including the use of proteasome inhibitors as anticancer agents. We examine their mechanisms of action, clinical efficacy, and limitations while exploring emerging strategies to overcome these challenges.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"246"},"PeriodicalIF":12.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12369272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977140","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":"Pyrotinib targeted EGFR/GRP78 mediated cell apoptosis in high EGFR gene copy number gastric cancer.","authors":"Lingbo Bao, Xudong Wang, Xiuyong Liao, Dong Li, ChunXue Li, Nan Dai, Xiaoyan Dai, Jing Yang, Nana Hu, Xueling Tong, Zhenjie He, Yuancheng Zhao, Zheng Liu, Yue Hu, Jinlu Shan, Dong Wang, Mengxia Li, Qian Chen","doi":"10.1186/s13046-025-03485-6","DOIUrl":"10.1186/s13046-025-03485-6","url":null,"abstract":"<p><strong>Background: </strong>Despite frequent Epidermal Growth Factor Receptor (EGFR) amplification and overexpression in gastric cancer, limited therapeutic responses were observed in existing EGFR-targeted agents. Pyrotinib, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor, has shown clinical efficacy in HER2-driven malignancies, but its potential role in EGFR-high copy number gastric cancer remains to be investigated.</p><p><strong>Methods: </strong>Using EGFR-high copy number gastric cancer cell lines, primary cells and subcutaneous tumor models in nude mice, we systematically evaluated pyrotinib's anti-tumor activity through viability assays, apoptosis analysis, and transcriptomic profiling. Mechanistic studies included co-immunoprecipitation, proximity ligation assays, ubiquitination assays, and RNA sequencing.</p><p><strong>Results: </strong>Pyrotinib selectively suppressed proliferation, induced apoptosis, and chemosensitized in EGFR-high copy number gastric cancer models. Mechanistically, pyrotinib promoted EGFR-GRP78 (Glucose-regulated protein 78) complex formation in the endoplasmic reticulum, activating the protein kinase R-like endoplasmic reticulum kinase/ activating transcription factor 4/ C-EBP homologous protein (PERK/ATF4/CHOP) axis to drive ER stress-mediated apoptosis. Concurrently, pyrotinib inhibited GRP78 phosphorylation at Thr62, triggering K48-linked ubiquitination (ubiquitin chains formed via lysine 48 linkages) and proteasomal degradation, which impaired DNA double-strand break (DSB) repair and sensitized cells to oxaliplatin-induced γ-H2A.X accumulation.</p><p><strong>Conclusion: </strong>This translational study suggests that pyrotinib combined with oxaliplatin may serve as a promising strategy for patients with EGFR-high copy number gastric cancer and highlighted the discovery of this previously unknown EGFR/ GRP78 signaling axis, which provides the molecular basis and the rationale to target EGFR.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"245"},"PeriodicalIF":12.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884204","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":"JNK pathway suppression mediates insensitivity to combination endocrine therapy and CDK4/6 inhibition in ER+ breast cancer.","authors":"Sarah Alexandrou, Christine S Lee, Kristine J Fernandez, Celine E Wiharja, Leila Eshraghi, John Reeves, Daniel A Reed, Neil Portman, Zoe Phan, Heloisa H Milioli, Iva Nikolic, Antonia L Cadell, David R Croucher, Kaylene J Simpson, Elgene Lim, Theresa E Hickey, Ewan K A Millar, Carla L Alves, Henrik J Ditzel, C Elizabeth Caldon","doi":"10.1186/s13046-025-03466-9","DOIUrl":"10.1186/s13046-025-03466-9","url":null,"abstract":"<p><p>CDK4/6 inhibitors in combination with endocrine therapy are now used as front-line treatment for patients with estrogen-receptor positive (ER+) breast cancer. While this combination improves overall survival, the mechanisms of disease progression remain poorly understood. Here, we performed unbiased genome-wide CRISPR/Cas9 knockout screens using endocrine sensitive ER+ breast cancer cells to identify novel drivers of resistance to combination endocrine therapy (tamoxifen) and CDK4/6 inhibitor (palbociclib) treatment. Our screens identified the inactivation of JNK signalling, including loss of the kinase MAP2K7, as a key driver of drug insensitivity. We developed multiple CRISPR/Cas9 knockout ER+ breast cancer cell lines (MCF-7 and T-47D) to investigate the effects of MAP2K7 and downstream MAPK8 and MAPK9 loss. MAP2K7 knockout increased metastatic burden in vivo and led to impaired JNK-mediated stress responses, as well as promoting cell survival and reducing senescence entry following endocrine therapy and CDK4/6 inhibitor treatment. Mechanistically, this occurred via loss of the AP-1 transcription factor c-JUN, leading to an attenuated response to combination endocrine therapy plus CDK4/6 inhibition. Furthermore, analysis of clinical datasets found that inactivation of the JNK pathway was associated with increased metastatic burden, and low pJNK^T183/Y185 activity correlated with a poorer response to systemic endocrine and CDK4/6 inhibitor therapies in both early-stage and metastatic ER+ breast cancer cohorts. Overall, we demonstrate that suppression of JNK signalling enables persistent growth during combined endocrine therapy and CDK4/6 inhibition. Our data provides the pre-clinical rationale to stratify patients based on JNK pathway activity prior to receiving combination endocrine therapy and CDK4/6 inhibition.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"244"},"PeriodicalIF":12.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876552","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":"COL10A1⁺ fibroblasts promote colorectal cancer metastasis and M2 macrophage polarization with pan-cancer relevance.","authors":"Shangshang Hu, Muzi Ding, Jinwei Lou, Jian Qin, Yuhan Chen, Zixuan Liu, Yue Li, Junjie Nie, Mu Xu, Huiling Sun, Xinliang Gu, Tao Xu, Shukui Wang, Shukui Wang, Yuqin Pan","doi":"10.1186/s13046-025-03510-8","DOIUrl":"10.1186/s13046-025-03510-8","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is a common gastrointestinal cancer with poor response to therapy and high metastatic risk. Cancer-associated fibroblasts (CAFs) support tumor progression, but their functional heterogeneity remains poorly understood.</p><p><strong>Methods: </strong>We integrated multi-omics data from 10,164 samples, including single-cell, bulk, spatial transcriptomics, and proteomics, to identify and characterize CAF subpopulations. Functional validation was performed using molecular assays, in vivo models, and drug screening.</p><p><strong>Results: </strong>We identified a COL10A1-positive fibroblast subpopulation (COL10A1⁺Fib) associated with CRC progression and poor patient prognosis. COL10A1⁺Fib promotes tumor cell proliferation, immune suppression, and metastasis. Mechanistically, COL10A1⁺Fib facilitates epithelial-mesenchymal transition (EMT) in CRC cells via COL10A1 secretion and induces M2 macrophage polarization through the COL10A1/CD18/JAK1/STAT3 signaling axis. In turn, M2 macrophages enhance COL10A1 expression in fibroblasts via the TGF-β/RUNX2 pathway, forming a pro-tumorigenic feedback loop. The DNA-PKcs inhibitor NU7441 reduces COL10A1 expression, suppresses CAF activity, and reverses EMT and M2 polarization. Pan-cancer analysis suggests that COL10A1⁺Fib may have similar functional roles across multiple major solid tumors.</p><p><strong>Conclusion: </strong>Our study identifies a CAF subpopulation, COL10A1⁺Fib, associated with CRC progression and immune suppression, suggesting it as a potential therapeutic target in CRC and possibly other malignancies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"243"},"PeriodicalIF":12.8,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876551","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":"TRIM6 ablation reverses ICB resistance in MSS gastric cancer by unleashing cGAS-STING-dependent antitumor immunity.","authors":"Yinan Niu, Chen Ding, Quansheng Wang, Jingyi Yin, Lingmeng Li, Wenshuai Liu, Xuefei Wang, Liyu Huang","doi":"10.1186/s13046-025-03513-5","DOIUrl":"10.1186/s13046-025-03513-5","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancers are classified into four molecular subtypes according to The Cancer Genome Atlas (TCGA) classification: Epstein-Barr virus-positive (EBV-positive), microsatellite instability-high (MSI-H), chromosomal instability (CIN), and genomically stable (GS). Unlike MSI-H gastric cancer, GS and CIN subtypes exhibit immunologically inert microenvironments and demonstrate minimal response to immune checkpoint blockade (ICB), necessitating novel strategies to overcome immunotherapy resistance.</p><p><strong>Methods: </strong>Through weighted gene co-expression network analysis (WGCNA), we identified the E3 ubiquitin ligase TRIM6 as inversely associated with MSI-H status. TRIM6-knockout murine models and subcutaneous tumors were subjected to flow cytometry, RNA sequencing, immunoblotting, and ubiquitination assays to characterize tumor-infiltrating lymphocytes (TILs), pathway activation, and TRIM6-mediated regulation of the cGAS-STING axis.</p><p><strong>Results: </strong>Hypermethylation-mediated TRIM6 downregulation distinguished MSI-H from microsatellite stable (MSS) gastric cancers. Clinically, TRIM6 expression inversely correlated with cytotoxic T lymphocyte (CTL) infiltration and anti-PD-1/PD-L1 therapeutic efficacy. Mechanistically, TRIM6 catalyzed K27-linked polyubiquitination of cGAS, triggering its proteasomal degradation and consequent suppression of the cGAS-STING pathway. TRIM6 ablation enhanced CD8⁺ T lymphocytes infiltration via cGAS-mediated innate immune response and synergized with anti-PD-L1 therapy in MSS gastric tumors.</p><p><strong>Conclusions: </strong>Our results elucidate TRIM6-mediated suppression of antitumor immunity as a novel mechanism underlying ICB resistance in MSS gastric cancer, positioning TRIM6 as both a predictive biomarker and therapeutic target for immunologically cold subtypes.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"242"},"PeriodicalIF":12.8,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859861","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":"Editorial expression of concern: ERRα suppression enhances the cytotoxicity of the MEK inhibitor trametinib against colon cancer cells.","authors":"Sheng Zhou, Hongwei Xia, Huanji Xu, Qiulin Tang, Yongzhan Nie, Qi Yong Gong, Feng Bi","doi":"10.1186/s13046-025-03507-3","DOIUrl":"10.1186/s13046-025-03507-3","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"241"},"PeriodicalIF":12.8,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856869","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":"MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodeling.","authors":"Marta Torrecilla-Parra, Virginia Pardo-Marqués, Antonio C Fuentes-Fayos, Miguel E G-García, Mario Fernández-de Frutos, José L López-Aceituno, Cristina Puigdueta, Carmen Zamora, Ana Pérez-García, Juan F Aranda, Rebeca Busto, Manuel D Gahete, Raúl M Luque, Cristina M Ramírez","doi":"10.1186/s13046-025-03504-6","DOIUrl":"10.1186/s13046-025-03504-6","url":null,"abstract":"<p><strong>Background: </strong>Due to the poor prognosis of patients suffering malignant brain tumors such as glioblastoma multiforme (GBM), the search for new therapeutic strategies with more efficacy and higher survival rate is of utmost urgency. Growing evidence suggests that alterations in autophagy and metabolism critically contribute to the pathogenesis and progression of GBM. In this context, microRNAs are known to regulate autophagy and associated cellular functions, which point them as promising therapeutic candidates. We previously established the role of miR-7 in regulating relevant metabolic pathways related to insulin signaling and cholesterol homeostasis.</p><p><strong>Methods: </strong>Bioinformatics analysis was performed to identify miR-7 target genes potentially involved in the regulation of metabolism and cellular processes related to GBM. Ectopic expression of miR-7 was assessed to investigate its role in macroautophagy and energy metabolism. In vivo, miR-7 levels were restored in a mouse GBM xenograft model to evaluate its potential therapeutic effect in already established tumors. Additional mechanistic approaches, including transcriptomics, bioinformatics, and histopathological analyses, indicate that miR-7 modifies the tumor phenotype by altering key genes involved in extracellular matrix (ECM) remodeling in vivo.</p><p><strong>Results: </strong>Herein, we unveiled new conceptual and functional pathophysiological avenues in GBM, with potential therapeutic implications, by demonstrating a novel dual role of miR-7 on the regulation of metabolism, through the impairment of the mitochondrial function and glycolysis, and autophagy, by inducing the initiation process through the regulation of PI3K/AKT/mTORC1 signaling, while blocking later stages via posttranscriptional inhibition of two key SNARE proteins, STX17 and SNAP29. Furthermore, in vivo studies using a preclinical model showed that miR-7 overexpression in already established GBM tumors promotes a significant inhibition of tumor size and progression and replicates the metabolic defects found in vitro. Moreover, our novel findings indicate that miR-7 modifies the tumor phenotype by promoting alterations in its mechanism of extracellular matrix remodeling in vivo.</p><p><strong>Conclusion: </strong>Altogether, our study provides solid, convincing evidence demonstrating that miR-7 might be used as a promising therapeutic target for GBM, paving the way to explore its potential as novel biomarker and actionable target candidate for this lethal cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"237"},"PeriodicalIF":12.8,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856871","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}