Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Blockade of αvβ6 and αvβ8 integrins with a chromogranin A-derived peptide inhibits TGFβ activation in tumors and suppresses tumor growth.","authors":"Anna Maria Gasparri, Arianna Pocaterra, Barbara Colombo, Giulia Taiè, Chiara Gnasso, Alessandro Gori, Federica Pozzi, Andrew Smith, Fulvio Magni, Alessia Ugolini, Matteo Doglio, Maria Chiara Bonini, Anna Mondino, Angelo Corti, Flavio Curnis","doi":"10.1186/s13046-025-03352-4","DOIUrl":"10.1186/s13046-025-03352-4","url":null,"abstract":"<p><strong>Background: </strong>The αvβ6- and αvβ8-integrins, two cell-adhesion receptors upregulated in many solid tumors, can promote the activation of transforming growth factor-β (TGFβ), a potent immunosuppressive cytokine, by interacting with the RGD sequence of the latency-associated peptide (LAP)/TGFβ complex. We have previously described a chromogranin A-derived peptide, called \"peptide 5a\", which recognizes the RGD-binding site of both αvβ6 and αvβ8 with high affinity and selectivity, and efficiently accumulates in αvβ6- or αvβ8-positive tumors. This study aims to demonstrate that peptide 5a can inhibit TGFβ activation in tumors and suppress tumor growth.</p><p><strong>Methods: </strong>Peptide 5a was chemically coupled to human serum albumin (HSA) to prolong its plasma half-life. The integrin recognition properties of this conjugate (called 5a-HSA) and its capability to block TGFβ activation by αvβ6⁺ and/or αvβ8⁺ cancer cells or by regulatory T cells (Tregs) were tested in vitro. The in vivo anti-tumor effects of 5a-HSA, alone and in combination with S-NGR-TNF (a vessel-targeted derivative of tumor necrosis factor-a), were investigated in various murine tumor models, including pancreatic ductal adenocarcinoma, fibrosarcoma, prostate cancer, and mammary adenocarcinoma.</p><p><strong>Results: </strong>In vitro assays showed that peptide 5a coupled to HSA maintains its capability of recognizing αvβ6 and αvβ8 with high affinity and selectivity and inhibits TGFβ activation mediated by αvβ6⁺ and/or αvβ8⁺ cancer cells, as well as by αvβ8⁺ Tregs. In vivo studies showed that systemic administration of 5a-HSA to tumor-bearing mice can reduce TGFβ signaling in neoplastic tissues and promote CD8-dependent anti-tumor responses. Combination therapy studies showed that 5a-HSA can enhance the anti-tumor activity of S-NGR-TNF, leading to tumor eradication.</p><p><strong>Conclusion: </strong>Peptide 5a is an efficient tumor-homing inhibitor of αvβ6- and αvβ8-integrin that after coupling to HSA, can be used as a drug to block integrin-dependent TGFβ activation in tumors and promote immunotherapeutic responses.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"88"},"PeriodicalIF":11.4,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587797","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":"Low-coverage whole genome sequencing of cell-free DNA to predict and track immunotherapy response in advanced non-small cell lung cancer.","authors":"Florian Janke, Mateo Gasser, Arlou K Angeles, Anja L Riediger, Magdalena Görtz, Louise Appenheimer, Astrid K Laut, Simon Ogrodnik, Sabrina Gerhardt, Albrecht Stenzinger, Marc A Schneider, Michael Thomas, Petros Christopoulos, Holger Sültmann","doi":"10.1186/s13046-025-03348-0","DOIUrl":"10.1186/s13046-025-03348-0","url":null,"abstract":"<p><strong>Background: </strong>Outcomes under anti-PD-(L)1 therapy have been variable in advanced non-small cell lung cancer (NSCLC) without reliable predictive biomarkers so far. Targeted next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) has demonstrated potential clinical utility to support clinical decisions, but requires prior tumor genetic profiling for proper interpretation, and wide adoption remains limited due to high costs.</p><p><strong>Methods: </strong>Tumor-agnostic low-coverage ctDNA whole genome sequencing (lcWGS) was used to longitudinally track genome-wide copy number variations (CNVs) and fragmentation features in advanced NSCLC patients (n = 118 samples from 49 patients) and healthy controls (n = 57). Tumor PD-L1 expression was available for comparison.</p><p><strong>Findings: </strong>Fragmentation features and CNVs were complementary indicators, whose combination significantly increased ctDNA detection compared to single-marker assessments (+ 20.3% compared to CNV analysis alone). Baseline fragment length alterations, but not CNVs, were significantly associated with subsequent progression-free survival (PFS; hazard ratio [HR] = 4.10, p = 6.58e-05) and could improve PFS predictions based on tumor PD-L1 expression alone (HR = 2.70, p = 0.019). Residual CNVs or aberrant fragmentation of ctDNA under ongoing therapy could stratify patients according to the subsequent response duration (median 5.8 vs. 47.0 months, p = 1.13e-06). The integrative analysis of ctDNA fragment characteristics at baseline, tumor PD-L1 expression, and residual ctDNA under ongoing treatment constituted the strongest independent predictor of PFS (p = 6.25e-05) and overall survival (p = 1.3e-03) in multivariable analyses along with other clinicopathologic variables.</p><p><strong>Interpretation: </strong>This study demonstrates the feasibility and potential clinical utility of lcWGS for the tumor-agnostic stratification and monitoring of advanced NSCLC under PD-(L)1 blockade based on CNV and fragmentomic profiling.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"87"},"PeriodicalIF":11.4,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587728","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":"Extraction of a stromal metastatic gene signature in breast cancer via spatial profiling.","authors":"Giorgio Bertolazzi, Valeria Cancila, Davide Vacca, Beatrice Belmonte, Daniele Lecis, Parsa Sirati Moghaddam, Arianna Di Napoli, Mario Paolo Colombo, Giancarlo Pruneri, Giannino Del Sal, Giorgio Scita, Matteo Fassan, Andrea Vecchione, Silvio Bicciato, Claudio Tripodo","doi":"10.1186/s13046-025-03353-3","DOIUrl":"10.1186/s13046-025-03353-3","url":null,"abstract":"<p><strong>Background: </strong>The identification of molecular features characterizing metastatic disease is a critical area of oncology research, as metastatic foci often exhibit distinct biological behaviors compared to primary tumors. While the focus has largely been on the neoplastic cells themselves, the characterization of the associated stroma remains largely underexplored, with significant implications for understanding metastasis.</p><p><strong>Main body: </strong>By employing spatially resolved transcriptomics, we analyzed the transcriptional features of primary breast adenocarcinoma and its associated metastatic foci, on a representative set of microregions. We identified a stromal metastatic (Met) signature, which was subsequently validated across transcriptomic reference human breast cancer (BC) datasets and in spatial transcriptomics of a murine model.</p><p><strong>Conclusion: </strong>We discuss the potential of a stromal Met signature to pinpoint metastatic breast cancer, serving as a prognostic tool that can provide a foundation for the exploration of tumor-extrinsic molecular hallmarks of BC metastatic foci.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"89"},"PeriodicalIF":11.4,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598238","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 chimeric antigen receptor tailored to integrate complementary activation signals potentiates the antitumor activity of NK cells.","authors":"Eunbi Yi, Eunbi Lee, Hyo Jin Park, Hyeon Ho Lee, So Hyeon Yun, Hun Sik Kim","doi":"10.1186/s13046-025-03351-5","DOIUrl":"10.1186/s13046-025-03351-5","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptors (CARs) are synthetic receptors that reprogram the target specificity and functions of CAR-expressing effector cells. The design of CAR constructs typically includes an extracellular antigen-binding moiety, hinge (H), transmembrane (TM), and intracellular signaling domains. Conventional CAR constructs are primarily designed for T cells but have been directly adopted for other effector cells, including natural killer (NK) cells, without tailored optimization. Given the benefits of CAR-NK cells over CAR-T cells in terms of safety, off-the-shelf utility, and antigen escape, there is an increasing emphasis on tailoring them to NK cell activation mechanisms.</p><p><strong>Methods: </strong>We first have taken a stepwise approach to modifying CAR components such as the combination and order of the H, TM, and signaling domains to achieve such tailoring in NK cells. Functionality of NK-tailored CARs were evaluated in vitro and in vivo in a model of CD19-expressing lymphoma, along with their expression and signaling properties in NK cells.</p><p><strong>Results: </strong>We found that NK-CAR driven by the synergistic combination of NK receptors NKG2D and 2B4 rather than DNAM-1 and 2B4 induces potent activation in NK cells. Further, more effective CAR-mediated cytotoxicity was observed following the sequential combination of DAP10, but not NKG2D TM, with 2B4 signaling domain despite the capacity of NKG2D TM to recruit endogenous DAP10 for signaling. Accordingly, an NK-CAR incorporating DAP10, 2B4, and CD3ζ signaling domains coupled to CD8α H and CD28 TM domains was identified as the most promising candidate to improve CAR-mediated cytotoxicity. This NK-tailored CAR provided more potent antitumor activity than a conventional T-CAR when delivered to NK cells both in vitro and in vivo.</p><p><strong>Conclusions: </strong>Hence, NK receptor-based domains hold great promise for the future of NK-CAR design with potentially significant therapeutic benefits.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"86"},"PeriodicalIF":11.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568715","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 blood-based liquid biopsy analyzing soluble immune checkpoints and cytokines identifies distinct neuroendocrine tumors.","authors":"Pablo Mata-Martínez, Lucía Celada, Francisco J Cueto, Gonzalo Sáenz de Santa María, Jaime Fernández, Verónica Terrón-Arcos, Nuria Valdés, Vanesa García Moreira, María Isabel Enguita Del Toro, Eduardo López-Collazo, María-Dolores Chiara, Carlos Del Fresno","doi":"10.1186/s13046-025-03337-3","DOIUrl":"10.1186/s13046-025-03337-3","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Neuroendocrine neoplasms (NENs) comprise a group of rare tumors originating from neuroendocrine cells, which are present in both endocrine glands and scattered throughout the body. Due to their scarcity and absence of specific markers, diagnosing NENs remains a complex challenge. Therefore, new biomarkers are required, ideally, in easy-to-obtain blood samples.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A panel of blood soluble immune checkpoints (sPD-L1, sPD-L2, sPD-1, sCD25, sTIM3, sLAG3, Galectin-9, sCD27, sB7.2 and sSIGLEC5) and cytokines (IL4, IL6, IP10 and MCP1) was quantified in a cohort of 139 NENs, including 29 pituitary NENs, 46 pheochromocytomas and paragangliomas, and 67 gastroenteropancreatic and pulmonary (GEPP) NENs, as well as in 64 healthy volunteers (HVs). The potential of these circulating immunological parameters to distinguish NENs from HVs, differentiate among various NENs subtypes, and predict their prognosis was evaluated using mathematical regression models. These immunological factors-based models generated scores that were evaluated by Receiver Operating Characteristic (ROC) and Area Under the Curve (AUC) analyses. Correlations between these scores and clinical data were performed. From these analyses, a minimal signature emerged, comprising the five shared immunological factors across the models: sCD25, sPD-L2, sTIM3, sLAG3, and Galectin-9. This refined signature was evaluated, validated, and checked for specificity against non-neuroendocrine tumors, demonstrating its potential as a clinically relevant tool for identifying distinct NENs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Most of the immunological factors analyzed showed specific expression patterns among different NENs. Scores based on signatures of these factors identified NENs with high efficiency, showing AUCs ranging between 0.948 and 0.993 depending on the comparison, and accuracies between 92.52% and 95.74%. These scores illustrated biological features of NENs including the similarity between pheochromocytomas and paragangliomas, the divergence between gastrointestinal and pulmonary NENs, and correlated with clinical features. Furthermore, the models demonstrated strong performance in distinguishing metastatic and exitus GEPP NENs, achieving sensitivities and specificities ranging from 80.95% to 88.89%. Additionally, an easy-to-implement minimal signature successfully identified all analyzed NENs with AUC values exceeding 0.900, and accuracies between 84.11% and 93.12%, which was internally validated by a discovery and validation randomization strategy. These findings highlight the effectiveness of the models and minimal signature in accurately diagnosing and differentiating NENs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The analysis of soluble immunological factors in blood presents a promising liquid biopsy approach for identifying NENs, delivering critical insights for both prognosis and diagnosis. This study serves as a proof-of-concept for an in","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"82"},"PeriodicalIF":11.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558673","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":"Multiple mechanisms and applications of tertiary lymphoid structures and immune checkpoint blockade.","authors":"Zelin Li, Shuhan Liu, Deyu Liu, Kangping Yang, Jing Xiong, Ziling Fang","doi":"10.1186/s13046-025-03318-6","DOIUrl":"10.1186/s13046-025-03318-6","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint blockade (ICB) inhibits tumor immune escape and has significantly advanced tumor therapy. However, ICB benefits only a minority of patients treated and may lead to many immune-related adverse events. Therefore, identifying factors that can predict treatment outcomes, enhance synergy with ICB, and mitigate immune-related adverse events is urgently needed.</p><p><strong>Main text: </strong>Tertiary lymphoid structures (TLS) are ectopic lymphoid tissues that arise from the tumor periphery. They have been found to be associated with better prognosis and improved clinical outcomes after ICB therapy. TLS may help address the problems associated with ICB. The multiple mechanisms of action between TLS and ICB remain unknown. This paper described potential mechanisms of interaction between the two and explored their potential applications.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"84"},"PeriodicalIF":11.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558675","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":"Head and neck tumor organoid biobank for modelling individual responses to radiation therapy according to the TP53/HPV status.","authors":"Christian Issing, Constantin Menche, Mara Romero Richter, Mohammed H Mosa, Jens von der Grün, Maximilian Fleischmann, Philipp Thoenissen, Ria Winkelmann, Tahmineh Darvishi, Andreas G Loth, Shahram Ghanaati, Franz Rödel, Peter J Wild, Christian H Brandts, Timo Stöver, Henner F Farin","doi":"10.1186/s13046-025-03345-3","DOIUrl":"10.1186/s13046-025-03345-3","url":null,"abstract":"<p><strong>Background: </strong>Head and neck cancers (HNC) represent an extremely heterogeneous group of diseases with a poorly predictable therapy outcome. Patient-derived tumor organoids (PDTO) offer enormous potential for individualized therapy testing and a better mechanistic understanding of the main HNC drivers.</p><p><strong>Methods: </strong>Here, we have established a comprehensive molecularly and functionally characterized head and neck organoid biobank (HNOB) recapitulating the clinically relevant subtypes of TP53 mutant and human papillomavirus type 16 (HPV 16) infection-driven HNC. Organoids were exposed to radiotherapy, and responses were correlated with clinical data. Genetically engineered normal and tumor organoids were used for testing the direct functional consequences of TP53-loss and HPV infection.</p><p><strong>Results: </strong>The HNOB consisting of 18 organoid models, including 15 tumor models, was generated. We identified subtype-associated transcriptomic signatures and pathological features, including sensitivity to TP53 stabilization by the MDM2 inhibitor Nutlin-3. Furthermore, we describe an in vitro radio response assay revealing phenotypic heterogeneity linked to the individual patient's treatment outcome, including relapse probability. Using genetically engineered organoids, the possibility of co-existence of both cancer drivers was confirmed. TP53 loss, as well as HPV, increased growth in normal and tumor organoids. TP53 loss-of-function alone was insufficient to promote radiation resistance, whereas HPV 16 oncogenes E6/E7 mediated radiosensitivity via induction of cell cycle arrest.</p><p><strong>Conclusion: </strong>Our results highlight the translational value of the head and neck organoid models not only for patient stratification but also for mechanistic validation of therapy responsiveness of specific cancer drivers.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"85"},"PeriodicalIF":11.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568717","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":"C-terminal binding protein-2 triggers CYR61-induced metastatic dissemination of osteosarcoma in a non-hypoxic microenvironment.","authors":"Laura Di Patria, Nadia Habel, Robert Olaso, Romain Fernandes, Catherine Brenner, Bojana Stefanovska, Olivia Fromigue","doi":"10.1186/s13046-025-03350-6","DOIUrl":"10.1186/s13046-025-03350-6","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma is the most prevalent cancer-related bone disease diagnosed in the pediatric age group. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and poor outcome. We established that the expression level of Cysteine-rich protein 61 (CYR61/CCN1) correlates to tumor neo-vascularization and dissemination in preclinical and clinical osteosarcoma samples. The aim of this study was to investigate the CYR61-related mechanisms leading to the acquisition of metastatic capacity by osteosarcoma cells.</p><p><strong>Methods: </strong>Transcriptomic data issued from RNA-seq were subjected to pathways and gene set enrichment analyses. Murine and human cell lines with overexpressed or downregulated C-terminal Binding protein 2 (CtBP2) were established by lentiviral transduction. Cell metabolic activity was assessed by Seahorse XF Analyzer; cell replication rate by BrdU incorporation assay; stemness by clonogenicity assay and RT-qPCR detection of markers; cell migration by wound healing assay and Boyden chambers system; cell invasion using Matrigel coated Boyden chambers or fluorescence microscopy of Matrigel embedded 3D spheroids. FFPE samples derived from syngeneic tumor cells grafts into BALB/c mice were analyzed by IHC. The protein interactome was predicted in silico using the STRING database.</p><p><strong>Results: </strong>GSEA revealed that CYR61 modulate the transcription process. The in vitro expression level of CtBP2 and Cyr61 correlated positively in a panel of osteosarcoma cell lines. In silico analysis of protein-protein interaction network revealed a link with stemness markers. Variations in CtBP2 expression levels influenced stemness markers expression levels, cell clonogenicity, cell migration, Matrix Metalloproteinase activity and cell invasion. Surprisingly, while induction of CtBP2 expression under CYR61 correlated with the metastatic dissemination process in vivo, it occurred only at the invasive front of tumors. Hypoxic conditions in central tumor region interfered with CtBP2 induction of expression.</p><p><strong>Conclusions: </strong>Our findings identify for the first time that CtBP2 acts as a required critical inducing factor in the CYR61-related metastatic progression of osteosarcoma, by favoring cell migration and invasiveness. Moreover, we demonstrate that while CtBP2 is a downstream transcriptional target of CYR61 signaling cascade, it occurs only under non-hypoxic conditions. The present study suggests that CtBP2 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"83"},"PeriodicalIF":11.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558674","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":"NONO regulates m⁵C modification and alternative splicing of PTEN mRNAs to drive gastric cancer progression.","authors":"Gaichao Zhao, Ruochen Liu, Lingjun Ge, Dan Qi, Qishu Wu, Zini Lin, Houji Song, Liping Zhong, Hongjuan Cui","doi":"10.1186/s13046-024-03260-z","DOIUrl":"10.1186/s13046-024-03260-z","url":null,"abstract":"<p><strong>Background: </strong>The effect of m⁵C modification on oncogene mRNAs has been well studied, while little is known about its influence on mRNAs of tumor suppressor genes (TSGs). Early studies showed PTEN, a key TSG, undergoes alternative splicing (AS) in cancers, however, the underlying regulatory mechanism remains elusive.</p><p><strong>Methods: </strong>We analyzed tissue microarrays and transcriptomic data derived from gastric cancer, with an emphasis on RNA splicing and m⁵C regulators. To unravel the role of NONO in GC, we employed RNA sequencing, RNA-Bis-Seq, RNA immunoprecipitation, RNA in situ hybridization, and Minigene reporter assay with NONO knockdown cells. The clinical relevance was validated using CDX models and human tissue microarrays.</p><p><strong>Results: </strong>Analysis of publicly available datasets and immunohistochemistry assay of tissue microarrays containing 40 GC tissues showed NONO was upregulated in GC and contributed to poor prognosis. In vitro and in vivo experiments indicated a positive regulatory role of NONO in terms of cell proliferation, migration, and invasion of GC. Mechanically, NONO interacted directly with PTEN pre-mRNA and recruited the RNA m⁵C methyltransferase NSUN2 via RNA-recognition motif (RRM) domains, altering the mRNA methylation pattern across PTEN pre-mRNA. The oncogenic role of NONO/NSUN2/PTEN axis in GC progression was further confirmed with pre-clinical experiments and clinical data.</p><p><strong>Conclusion: </strong>Here, we revealed NONO-regulated AS of PTEN mRNA in an m⁵C-dependent manner, resulting in the downregulation of PTEN expression in gastric cancer (GC).This study unveils a novel regulatory mechanism of tumor suppressor gene inactivation mediated by m⁵C modification and related alternative splicing in cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"81"},"PeriodicalIF":11.4,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544245","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":"Exosome-transmitted LUCAT1 promotes stemness transformation and chemoresistance in bladder cancer by binding to IGF2BP2.","authors":"Yonghao Zhan, Zhenzhen Zhou, Zhaowei Zhu, Lianghao Zhang, Shuanbao Yu, Yuchen Liu, Xuepei Zhang","doi":"10.1186/s13046-025-03330-w","DOIUrl":"10.1186/s13046-025-03330-w","url":null,"abstract":"<p><p>The chemotherapy resistance is an awkward challenge in management of bladder cancer (BC). Cancer organoid model is an effective preclinical tumor model that could faithfully represent clinical manifestations and simulate the biological processes of chemoresistance. Recent studies have revealed that cancer stem cells (CSCs) play a significant role in the development of chemoresistance in cancer. Exosomes act as essential intercellular messengers and participate in controlling the conversion of distinct cell characteristics, including chemoresistance. However, the role of exosome-transmitted lncRNAs in bladder cancer chemoresistance has rarely been reported. In this study, cancer organoid models were developed from urothelial carcinomas to explore the pathophysiology mechanism of BC chemoresistance, and RNA-seq was performed to screen for lncRNAs involved in chemoresistance of BC. We found chemotherapy enriches stem-like cells in BC, and significant upregulation of Lung Cancer Associated Transcript 1 (LUCAT1) occurs in chemotherapy-resistant organoids and correlated with chemotherapy response. Further experimental results demonstrated that LUCAT1 promotes chemoresistance in bladder cancer by enhancing the stemness phenotype of BC cells in vivo and in vitro. Moreover, exosomes derived from bladder cancer stem cells can enhance the stemness phenotype and chemoresistance of BC cells by delivering LUCAT1. Mechanistically, LUCAT1 could significantly enhance the mRNA stability of HMGA1 via binding to IGF2BP2 in an m6A-dependent manner. The study demonstrates an important role for exosome-transmitted LUCAT1 in chemoresistance and LUCAT1 has the potential to function as both a diagnostic biomarker and therapeutic target for BC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"80"},"PeriodicalIF":11.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537896","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}