Journal of Experimental & Clinical Cancer Research最新文献

{"title":"AMP-activated protein kinase mediates adaptation of glioblastoma cells to conditions of the tumor microenvironment.","authors":"Nadja I Lorenz, Benedikt Sauer, Hans Urban, Jan-Béla Weinem, Bhavesh S Parmar, Pia S Zeiner, Maja I Strecker, Dorothea Schulte, Michel Mittelbronn, Tijna Alekseeva, Lisa Sevenich, Patrick N Harter, Christian Münch, Joachim P Steinbach, Anna-Luisa Luger, Dieter Henrik Heiland, Michael W Ronellenfitsch","doi":"10.1186/s13046-025-03346-2","DOIUrl":"https://doi.org/10.1186/s13046-025-03346-2","url":null,"abstract":"<p><p>AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolic activity. We hypothesized that in glioblastoma (GB), AMPK plays a pivotal role in balancing metabolism under conditions of the tumor microenvironment with fluctuating and often low nutrient and oxygen availability. Impairment of this network could thus interfere with tumor progression. AMPK activity was modulated genetically by CRISPR/Cas9-based double knockout (DKO) of the catalytic α1 and α2 subunits in human GB cells and effects were confirmed by pharmacological AMPK inhibition using BAY3827 and an inactive control compound in primary GB cell cultures. We found that metabolic adaptation of GB cells under energy stress conditions (hypoxia, glucose deprivation) was dependent on AMPK and accordingly that AMPK DKO cells were more vulnerable to glucose deprivation or inhibition of glycolysis and sensitized to hypoxia-induced cell death. This effect was rescued by reexpression of the AMPK α2 subunit. Similar results were observed using the selective pharmacological AMPK inhibitor BAY3827. Mitochondrial biogenesis was regulated AMPK-dependently with a reduced mitochondrial mass and mitochondrial membrane potential in AMPK DKO GB cells. In vivo, AMPK DKO GB cells showed impaired tumor growth and tumor formation in CAM assays as well as in an orthotopic glioma mouse model. Our study highlights the importance of AMPK for GB cell adaptation towards energy depletion and emphasizes the role of AMPK for tumor formation in vivo. Moreover, we identified mitochondria as central downstream effectors of AMPK signaling. The development of AMPK inhibitors could open opportunities for the treatment of hypoxic tumors.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"104"},"PeriodicalIF":11.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694303","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":"Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism.","authors":"Ielizaveta Gorodetska, Vasyl Lukiyanchuk, Marta Gawin, Myroslava Sliusar, Annett Linge, Fabian Lohaus, Tobias Hölscher, Kati Erdmann, Susanne Fuessel, Angelika Borkowetz, Anna Wojakowska, Daniel Fochtman, Mark Reardon, Ananya Choudhury, Yasmin Antonelli, Aldo Leal-Egaña, Ayse Sedef Köseer, Uğur Kahya, Jakob Püschel, Andrea Petzold, Daria Klusa, Claudia Peitzsch, Romy Kronstein-Wiedemann, Torsten Tonn, Lukasz Marczak, Christian Thomas, Piotr Widłak, Monika Pietrowska, Mechthild Krause, Anna Dubrovska","doi":"10.1186/s13046-025-03299-6","DOIUrl":"https://doi.org/10.1186/s13046-025-03299-6","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PCa) is the second most common type of tumor diagnosed in men and the fifth leading cause of cancer-related death in male patients. The response of metastatic disease to standard treatment is heterogeneous. As for now, there is no curative treatment option available for metastatic PCa, and the clinical tests capable of predicting metastatic dissemination and metastatic response to the therapies are lacking. Our recent study identified aldehyde dehydrogenases ALDH1A1 and ALDH1A3 as critical regulators of PCa metastases. Still, the exact mechanisms mediating the role of these proteins in PCa metastatic dissemination remain not fully understood, and plasma-based biomarkers of these metastatic mechanisms are not available.</p><p><strong>Methods: </strong>Genetic silencing, gene overexpression, or treatment with different concentrations of the retinoic acid (RA) isomers, which are the products of ALDH catalytic activity, were used to modulate the interplay between retinoic acid receptors (RARs) and androgen receptor (AR). RNA sequencing (RNAseq), reporter gene assays, and chromatin immunoprecipitation (ChIP) analysis were employed to validate the role of RARs and AR in the regulation of the transforming growth factor-beta 1 (TGFB1) expression. Gene expression levels of ALDH1A1, ALDH1A3, and the matrix metalloproteinase 11 (MMP11) and their correlation with pathological parameters and clinical outcomes were analysed by mining several publicly available patient datasets as well as our multi-center transcriptomic dataset from patients with high-risk and locally advanced PCa. The level of MMP11 protein was analysed by enzyme-linked immunosorbent assay (ELISA) in independent cohorts of plasma samples from patients with primary or metastatic PCa and healthy donors, while plasma proteome profiles were obtained for selected subsets of PCa patients.</p><p><strong>Results: </strong>We could show that ALDH1A1 and ALDH1A3 genes differently regulate TGFB1 expression in a RAR- and AR-dependent manner. We further observed that the TGF-β1 pathway contributes to the regulation of the MMPs, including MMP11. We have confirmed the relevance of MMP11 as a promising clinical marker for PCa using several independent gene expression datasets. Further, we have validated plasma MMP11 level as a prognostic biomarker in patients with metastatic PCa. Finally, we proposed a hypothetical ALDH1A1/MMP11-related plasma proteome-based prognostic signature.</p><p><strong>Conclusions: </strong>TGFB1/MMP11 signaling contributes to the ALDH1A1-driven PCa metastases. MMP11 is a promising blood-based biomarker of PCa progression.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"105"},"PeriodicalIF":11.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694304","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":"Proteomic profiling and functional analysis of extracellular vesicles from metastasis-competent circulating tumor cells in colon cancer.","authors":"Luis Enrique Cortés-Hernández, Zahra Eslami-S, Aurore Attina, Silvia Batista, Laure Cayrefourcq, Jérôme Vialeret, Dolores Di Vizio, Christophe Hirtz, Bruno Costa-Silva, Catherine Alix-Panabières","doi":"10.1186/s13046-025-03360-4","DOIUrl":"10.1186/s13046-025-03360-4","url":null,"abstract":"<p><strong>Background: </strong>Circulating tumor cells (CTCs) are pivotal in cancer progression, and in vitro CTC models are crucial for understanding their biological mechanisms. This study focused on the characterization of extracellular vesicles (EVs) from CTC lines derived from a patient with metastatic colorectal cancer (mCRC) at different stages of progression who progressed despite therapy (thus mirroring the clonal evolution of cancer).</p><p><strong>Methods and results: </strong>Morphological and size analyses revealed variations among EVs derived from different CTC lines. Compared with the Vesiclepedia database, proteomic profiling of these EVs revealed enrichment of proteins related to stemness, endosomal biogenesis, and mCRC prognosis. Integrin family proteins were significantly enriched in EVs from CTC lines derived after therapy failure. The role of these EVs in cancer progression was analyzed by assessing their in vivo distribution, particularly in the liver, lungs, kidneys, and bones. EVs accumulate significantly in the liver, followed by the lungs, kidneys and femurs.</p><p><strong>Conclusions: </strong>This study is a pioneering effort in highlighting therapy progression-associated changes in EVs from mCRC patients via an in vitro CTC model. The results offer insights into the role of metastasis initiator CTC-derived EVs in cancer spread, suggesting their utility for studying cancer tissue distribution mechanisms. However, these findings must be confirmed and extended to patients with mCRC. This work underscores the potential of CTC-derived EVs as tools for understanding cancer dissemination.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"102"},"PeriodicalIF":11.4,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677402","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":"N⁴-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma.","authors":"Leyi Huang, Yanan Lu, Rihua He, Xiaofeng Guo, Jiajia Zhou, Zhiqiang Fu, Jingwen Li, Jianping Liu, Rufu Chen, Yu Zhou, Quanbo Zhou","doi":"10.1186/s13046-025-03362-2","DOIUrl":"10.1186/s13046-025-03362-2","url":null,"abstract":"<p><strong>Background: </strong>Perineural invasion (PNI) is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC), which occurs at a high incidence and significantly contributes to PDAC lethality and poor survival. Despite its prevalence and association with poor prognosis, the molecular mechanisms underlying PNI in PDAC remain unclear.</p><p><strong>Methods: </strong>We investigated clinical samples from two cohorts by UPLC/MS-MS to profiled significantly altered chemical RNA modifications in PDAC tissues with PNI lesions. Dorsal root ganglion coculture systems and sciatic nerve injection models validated PNI ability. We combined RNA-seq, acRIP-seq and ac4C-seq with CRISPR-based techniques to explore the regulatory mechanism of ac4C modification on the integrin beta 5 (ITGB5) transcript.</p><p><strong>Result: </strong>We reported that N⁴-acetylcytidine (ac4C) is a significantly altered chemical RNA modification in PDAC tissues with PNI lesions. In vitro and in vivo models demonstrated that tumor cells overexpression of N-acetyltransferase 10 (NAT10), the writer enzyme of mRNA ac4C modification, enhances PNI in PDAC. Further analysis revealed decreased ac4C levels on transcripts of the focal adhesion pathway, particular on ITGB5, in NAT10-knockdown PDAC cells. This ac4C modification in the CDS region of ITGB5 mRNA promotes its stability, subsequently activating the ITGB5-pFAK-pSrc pathway. CRISPR-based analysis further confirmed the crucial role of NAT10-mediated ac4C modification in regulating ITGB5 expression. Combining small-molecule inhibitors targeting NAT10 and focal adhesion kinase (FAK) significantly attenuated PNI in vivo.</p><p><strong>Conclusion: </strong>Our findings reveal a previously unrecognized ac4C-mediated epigenetic mechanism in PNI and propose a novel therapeutic strategy to improve survival in PDAC patients. NAT10 promotes PNI via ac4C modification in PDAC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"103"},"PeriodicalIF":11.4,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677401","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: Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2- mediated ATOH8 transcriptional repression.","authors":"Yi Zhang, Bo Tang, Jun Song, Shuiping Yu, Yang Li, Huizhao Su, Songqing He","doi":"10.1186/s13046-025-03364-0","DOIUrl":"10.1186/s13046-025-03364-0","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"101"},"PeriodicalIF":11.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671707","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":"CircPVT1 weakens miR-33a-5p unleashing the c-MYC/GLS1 metabolic axis in breast cancer.","authors":"Alina Catalina Palcau, Claudio Pulito, Valentina De Pascale, Luca Casadei, Mariacristina Valerio, Andrea Sacconi, Valeria Canu, Daniela Rutigliano, Sara Donzelli, Federica Lo Sardo, Francesca Romana Auciello, Fulvia Pimpinelli, Paola Muti, Claudio Botti, Sabrina Strano, Giovanni Blandino","doi":"10.1186/s13046-025-03355-1","DOIUrl":"10.1186/s13046-025-03355-1","url":null,"abstract":"<p><strong>Background: </strong>Altered metabolism is one of the cancer hallmarks. The role of circRNAs in cancer metabolism is poorly studied. Specifically, the impact of circPVT1, a well-known oncogenic circRNA on triple negative breast cancer metabolism is mechanistically underexplored.</p><p><strong>Methods: </strong>The clinical significance of circPVT1 expression levels was assessed in human breast cancer samples using digital PCR and the cancer genome atlas (TCGA) dataset. The oncogenic activity of circPVT1 was assessed in TNBC cell lines and in MCF-10 A breast cell line by either ectopic expression or depletion of circPVT1 molecule. CircPVT1 mediated metabolic perturbation was assessed by 1 H-NMR spectroscopy metabolic profiling. The binding of circPVT1 to miR-33a-5p and c-Myc recruitment onto the Glutaminase gene promoter were assessed by RNA immunoprecipitation and chromatin immunoprecipitation assays, respectively. The circPVT1/miR-33a-5p/Myc/GLS1 axis was functionally validated in breast cancer patients derived organoids. The viability of 2D and PDO cell models was assessed by ATP light assay and Opera Phenix plus high content screening.</p><p><strong>Results: </strong>We initially found that the expression of circPVT1 was significantly higher in tumoral tissues than in non-tumoral breast tissues. Basal like breast cancer patients with higher levels of circPVT1 exhibited shorter disease-free survival compared to those with lower expression. CircPVT1 ectopic expression rendered fully transformed MCF-10 A immortalized breast cells and increased tumorigenicity of TNBC cell lines. Depletion of endogenous circPVT1 reduced tumorigenicity of SUM-159PT and MDA-MB-468 cells. 1 H-NMR spectroscopy metabolic profiling of circPVT1 depleted breast cancer cell lines revealed reduced glycolysis and glutaminolitic fluxes. Conversely, MCF-10 A cells stably overexpressing circPVT1 exhibited increased glutaminolysis. Mechanistically, circPVT1 sponges miR-33a-5p, a well know metabolic microRNA, which in turn releases c-MYC activity promoting transcriptionally glutaminase. This activity facilitates the conversion of glutamine to glutamate. CircPVT1 depletion synergizes with GLS1 inhibitors BPTES or CB839 to reduce cell viability of breast cancer cell lines and breast cancer-derived organoids.</p><p><strong>Conclusions: </strong>In aggregate, our findings unveil the circPVT1/miR-33a-5p/Myc/GLS1 axis as a pro-tumorigenic metabolic event sustaining breast cancer transformation with potential therapeutic implications.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"100"},"PeriodicalIF":11.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671703","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":"PHGDH activation fuels glioblastoma progression and radioresistance via serine synthesis pathway.","authors":"Xiaojin Liu, Bangxin Liu, Junwen Wang, Hongbin Liu, Jiasheng Wu, Yiwei Qi, Yuan Liu, Hongtao Zhu, Chaoxi Li, Liu Yang, Jian Song, Guojie Yao, Weidong Tian, Kai Zhao, Lin Han, Kai Shu, Suojun Zhang, Jianghong Man, Chao You, Haohao Huang, Ran Li","doi":"10.1186/s13046-025-03361-3","DOIUrl":"10.1186/s13046-025-03361-3","url":null,"abstract":"<p><strong>Background: </strong>Glioma stem-like cells (GSCs) are key drivers of treatment resistance and recurrence in glioblastoma (GBM). Phosphoglycerate dehydrogenase (PHGDH), a crucial enzyme in the de novo serine synthesis pathway (SSP), is implicated in tumorigenesis and therapy resistance across various cancers. However, its specific role in GBM, particularly in radioresistance, remains poorly understood.</p><p><strong>Methods: </strong>In silico analysis of GBM patient data assessed SSP enrichment and PHGDH expression linked with tumor stemness. Comparative gene expression analysis focused on PHGDH in paired GBM specimens and GSCs. Genetic and pharmacological loss-of-function assays were performed in vitro and in vivo to evaluate PHGDH's impact on GSC self-renewal and malignant progression. Comprehensive transcriptomic and metabolomic analyses, along with chromatin immunoprecipitation, mass spectrometry, and various other biochemical assays, were used to elucidate PHGDH-mediated mechanisms in GBM progression and radioresistance.</p><p><strong>Results: </strong>PHGDH expression is significantly elevated in GSCs, associated with aggressive glioma progression and poor clinical outcomes. PHGDH activation enhances GSC self-renewal by regulating redox homeostasis, facilitating one-carbon metabolism, and promoting DNA damage response via SSP activation. Importantly, MYC was identified as a crucial transcriptional regulator of PHGDH expression. Furthermore, genetic ablation or pharmacological inhibition of PHGDH markedly reduced tumor growth and increased tumor sensitivity to radiotherapy, thereby improving survival outcomes in orthotopic GSC-derived and patient-derived GBM xenograft models.</p><p><strong>Conclusions: </strong>This study underscores the pivotal role of MYC-mediated PHGDH activation in driving GSC malignant progression and radioresistance in GBM. Targeting PHGDH presents a promising approach to enhance radiotherapy efficacy in GBM patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"99"},"PeriodicalIF":11.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659247","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":"Are monocytes a preferable option to develop myeloid cell-based therapies for solid tumors?","authors":"Daisy Bhatia, Riccardo Dolcetti, Roberta Mazzieri","doi":"10.1186/s13046-025-03359-x","DOIUrl":"10.1186/s13046-025-03359-x","url":null,"abstract":"<p><p>In the last two decades, novel and promising cell-based therapies have populated the treatment landscape for haematological tumors. However, commonly exploited T and NK cell-based therapies show limited applicability to solid tumors. This is mainly given by the impaired tumor trafficking capability and limited effector activity of these cells within a highly immunosuppressive tumor microenvironment. Myeloid cells spontaneously home to tumors and can thus be reprogrammed and/or engineered to directly attack tumor cells or locally and selectively deliver therapeutically relevant payloads that may improve the efficacy of immunotherapy against difficult-to-access solid tumors. In the context of myeloid cell-based therapies, adoptive transfer of monocytes has often been overshadowed by infusion of differentiated macrophages or hematopoietic stem cell transplantation despite their promising therapeutic potential. Here, we summarize the recent improvements and benefits of using monocytes for the treatment of solid tumors, their current clinical applications and the challenges of their use as well as some possible strategies to overcome them.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"98"},"PeriodicalIF":11.4,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634861","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":"Viral expression of NE/PPE enhances anti-colorectal cancer efficacy of oncolytic adenovirus by promoting TAM M1 polarization to reverse insufficient effector memory/effector CD8⁺ T cell infiltration.","authors":"Shuo Wang, Lingkai Kong, Linpei Wang, Yan Zhuang, Ciliang Guo, Yuxin Zhang, Huawei Cui, Xiaosong Gu, Junhua Wu, Chunping Jiang","doi":"10.1186/s13046-025-03358-y","DOIUrl":"10.1186/s13046-025-03358-y","url":null,"abstract":"<p><strong>Background: </strong>Oncolytic adenoviruses are among the most widely utilized oncolytic viruses due to their notable anti-tumor and gene expression capabilities, and modification of ADVs to create armed adenoviruses remains a popular research direction. Nonetheless, immune suppression triggered by ADV and targeted enhancements based on this limitation have been relatively unexplored.</p><p><strong>Methods: </strong>Flow cytometry was employed to assess immune infiltration in the tumor microenvironment following ADV therapy. Targeted novel recombinant oncolytic viruses, ADV^NE and ADV^PPE, were designed, and their antitumor efficacy, safety, and ability to reshape immune infiltration were evaluated in both subcutaneous tumor models in mice and in vitro experiments. Immune cell depletion assays confirmed the critical role of macrophages. The impact of HMGB1 on macrophage polarization was investigated using shRNA, qRT-PCR, ELISA, and flow cytometry. Furthermore, the importance of TLR4 and its downstream pathways was validated through immunoprecipitation, Western blotting, homozygous knockout mice, and TLR4 inhibitors.</p><p><strong>Results: </strong>We demonstrated that ADV limits the infiltration of effector memory/effector CD8 + T cells (T_EM/T_E) within the tumor microenvironment. To address this, we leveraged the strong capacity of NE or PPE to recruit T_EM/T_E by constructing novel recombinant oncolytic adenoviruses, ADV^NE or ADV^PPE, armed with NE or PPE. These recombinant viruses induce pyroptosis in colorectal cancer cells accompanied by the release of HMGB1. HMGB1 binds to TLR4 on the surface of macrophages, activating the MyD88-NFκB-NLRP3 (ASC) pathway and promoting M1 polarization of TAMs, thereby increasing T_EM/T_E cell infiltration and enhancing antitumor efficacy.</p><p><strong>Conclusions: </strong>In summary, this study presents the development of the novel oncolytic adenoviruses ADV^NE and ADV^PPE with enhanced anti-tumor efficacy and provides an in-depth exploration of their specific anti-tumor mechanisms. These findings indicate promising clinical therapeutic prospects and offer new insights for advancing oncolytic adenovirus therapies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"97"},"PeriodicalIF":11.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626705","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-1297 is frequently downmodulated in flat epithelial atypia of the breast and promotes mammary neoplastic transformation via EphrinA2 regulation.","authors":"Giorgia Scafetta, Gian Luca Rampioni Vinciguerra, Simona Giglio, Omar Faruq, Roberto Cirombella, Ilenia Segatto, Francesca Citron, Maria Chiara Mattevi, Elisabetta Di Renzi, Luciano Cascione, Pierluigi Gasparini, Barbara Belletti, Gustavo Baldassarre, Andrea Sacconi, Giovanni Blandino, Andrea Vecchione","doi":"10.1186/s13046-025-03354-2","DOIUrl":"10.1186/s13046-025-03354-2","url":null,"abstract":"<p><p>Breast cancer ranks as the most prevalent form of cancer globally. Currently, advanced screening methods have significantly improved early detection rates. These achievements have led to more non-invasive cancer diagnoses and underscored the clinical relevance of precursor lesions like flat epithelial atypia (FEA), a histological condition characterized by mild atypical changes in the normal epithelium lining the mammary ducts. Despite the increasing detection of FEA in mammary biopsy, our understanding of the biological behavior of this entity remains limited and, as a consequence, the clinical management of patients is still being debated. Evidence from the literature indicates that dysregulation of microRNAs contributes to all stages of breast cancer progression, potentially serving as valuable markers of disease evolution. In this study, through a comparison of the microRNA profiles of normal mammary epithelium, FEA, and non-invasive breast cancer in three cohorts of patients, we identified downregulation of miR-1297 as a common feature in both FEA and non-invasive breast cancer compared to the normal counterpart. Mechanistically, overexpression of miR-1297 inhibits the growth of breast cancer cells by targeting the oncogenic receptor tyrosine kinase EphrinA2. In contrast, downregulation of miR-1297 increases proliferation and alters the morphology of normal mammary epithelial cells in a three-dimensional context. These findings pinpoint the downregulation of miR-1297 as an early event in mammary transformation and suggest its potential role as a driver of progression in FEA, harboring the capacity to evolve into malignancy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"96"},"PeriodicalIF":11.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626704","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}