Journal of Experimental & Clinical Cancer Research最新文献

{"title":"SNORA37/CMTR1/ELAVL1 feedback loop drives gastric cancer progression via facilitating CD44 alternative splicing.","authors":"Banghe Bao, Minxiu Tian, Xiaojing Wang, Chunhui Yang, Jiaying Qu, Shunchen Zhou, Yang Cheng, Qiangsong Tong, Liduan Zheng","doi":"10.1186/s13046-025-03278-x","DOIUrl":"10.1186/s13046-025-03278-x","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence shows that small nucleolar RNA (snoRNA), a type of highly conserved non-coding RNA, is involved in tumorigenesis and aggressiveness. However, the roles of snoRNAs in regulating alternative splicing crucial for cancer progression remain elusive.</p><p><strong>Methods: </strong>High-throughput RNA sequencing and comprehensive analysis were performed to identify crucial snoRNAs and downstream alternative splicing events. Biotin-labeled RNA pull-down, mass spectrometry, cross-linking RNA immunoprecipitation, and in vitro binding assays were applied to explore interaction of snoRNAs with protein partners. Alternative splicing and gene expression was observed by real-time quantitative RT-PCR and western blot assays. In vitro and in vivo studies were performed to investigate biological effects of snoRNAs and their protein partners in gastric cancer. Survival analysis was undertaken by using Kaplan-Meier method and log-rank test.</p><p><strong>Results: </strong>SNORA37 was identified as an up-regulated snoRNA essential for tumorigenesis and aggressiveness of gastric cancer. Gain- and loss-of-function studies indicated that SNORA37 promoted the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. Mechanistically, as an ELAV like RNA binding protein 1 (ELAVL1)-generated snoRNA, SNORA37 directly bound to cap methyltransferase 1 (CMTR1) to facilitate its interaction with ELAVL1, resulting in nuclear retention and activity of ELAVL1 in regulating alternative splicing of CD44. Rescue studies revealed that SNORA37 exerted oncogenic roles in gastric cancer progression via facilitating CMTR1-ELAVL1 interaction. In clinical gastric cancer cases, high levels of SNORA37, CMTR1, ELAVL1, or CD44 were associated with shorter survival and poor outcomes of patients.</p><p><strong>Conclusions: </strong>These results indicated that SNORA37/CMTR1/ELAVL1 feedback loop drives gastric cancer progression via facilitating CD44 alternative splicing.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"15"},"PeriodicalIF":11.4,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015371","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":"Identification and characterization of tumor and stromal derived liquid biopsy analytes in pancreatic ductal adenocarcinoma.","authors":"Julian Götze, Kira Meißner, Thais Pereira-Veiga, Yassine Belloum, Svenja Schneegans, Jolanthe Kropidlowski, Joao Gorgulho, Alina Busch, Kim Christin Honselmann, Martin Schönrock, Arne Putscher, Sven Peine, Christine Nitschke, Ronald Simon, Volker Spindler, Jakob Robert Izbicki, Thilo Hackert, Carsten Bokemeyer, Klaus Pantel, Faik Güntaç Uzunoglu, Marianne Sinn, Harriet Wikman","doi":"10.1186/s13046-024-03262-x","DOIUrl":"10.1186/s13046-024-03262-x","url":null,"abstract":"<p><strong>Background: </strong>The lack of predictive biomarkers contributes notably to the poor outcomes of patients with pancreatic ductal adenocarcinoma (PDAC). Cancer-associated fibroblasts (CAFs) are the key components of the prominent PDAC stroma. Data on clinical relevance of CAFs entering the bloodstream, known as circulating CAFs (cCAFs) are scarce. Here, we developed a combined liquid biopsy assay to detect cCAFs and circulating tumor cells (CTCs) in metastatic PDAC (mPDAC) and other metastatic gastrointestinal malignancies (mGI). In addition, we evaluated plasma hyaluronan (HA) levels as a complementary surrogate biomarker of the stromal extent in patients with PDAC.</p><p><strong>Methods: </strong>A sequential liquid biopsy assay based on a two step-enrichment, combining marker dependent and independent cell enrichment, was established for cCAF and CTC detection and validated in mPDAC and mGI patients. The enriched cells were identified by multiplex immunofluorescence. HA measurement was performed by ELISA on blood samples from healthy blood donors (HD), localized and late-stage PDAC patients.</p><p><strong>Results: </strong>cCAFs (≥ 1cCAFs/7.5 mL blood) were detected in 95.4% of mPDAC and in 78.2% of mGI patients, with significantly higher numbers in mPDAC compared to mGI patients (mean number 22.7 vs. 11.0; P = 0.0318). mPDAC patients with ≥ 15 cCAFs/7.5 mL blood had a significant shorter median overall survival (mOS 3.2 months (95% confidence interval (CI) 0.801-5.855) vs. 14.2 months (95% CI 6.055-22.332); P = 0.013), whereby CTC levels were not associated with mOS. In mGI neither cCAFs nor CTCs had a significant impact on OS. HA plasma levels in mPDAC patients were significantly higher compared to HD (mean 123.0 ng/mL vs. 74.45 ng/mL, P = 0.015). High HA in localized and late-stage PDAC were associated with a significantly shorter mOS (mOS_{localized PDAC}: 12.6 months vs. 23.5 months (P = 0.008); mOS_mPDAC: 1.8 months vs. 5.3 months (P = 0.004)).</p><p><strong>Conclusions: </strong>Our liquid biopsy assay provides robust detection of cCAFs in mPDAC and mGI patients. The measurement of both circulatory stromal parameters, cCAFs and HA, adds valuable clinical information as they are associated with an unfavorable outcome in PDAC. These results highlight that stromal characteristics unique to PDAC could be leveraged to fill the current gap in discovering predictive biomarkers.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"14"},"PeriodicalIF":11.4,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015355","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 of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma.","authors":"Daniel Oyon, Amaya Lopez-Pascual, Borja Castello-Uribe, Iker Uriarte, Giulia Orsi, Sofia Llorente, Jasmin Elurbide, Elena Adan-Villaescusa, Emiliana Valbuena-Goiricelaya, Ainara Irigaray-Miramon, Maria Ujue Latasa, Luz A Martinez-Perez, Luca Reggiani Bonetti, Felipe Prosper, Mariano Ponz-Sarvise, Silvestre Vicent, Antonio Pineda-Lucena, David Ruiz-Clavijo, Bruno Sangro, Urko Aguirre Larracoechea, Tian V Tian, Andrea Casadei-Gardini, Irene Amat, Maria Arechederra, Carmen Berasain, Jesus M Urman, Matias A Avila, Maite G Fernandez-Barrena","doi":"10.1186/s13046-024-03268-5","DOIUrl":"10.1186/s13046-024-03268-5","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options and a poor prognosis. The critical role of epigenetic alterations such as changes in DNA methylation, histones modifications, and chromatin remodeling, in pancreatic tumors progression is becoming increasingly recognized. Moreover, in PDAC these aberrant epigenetic mechanisms can also limit therapy efficacy. This study aimed to investigate the expression and prognostic significance of a key epigenetic complex encompassing DNA methyltransferase-1 (DNMT1), the histone methyltransferase G9a, and the scaffold protein UHRF1 in PDAC. We also evaluated the therapeutic potential of an innovative inhibitor targeting these epigenetic effectors.</p><p><strong>Methods: </strong>Immunohistochemical analysis of DNMT1, G9a, and UHRF1 expression was conducted in human PDAC tissue samples. Staining was semi-quantitatively scored, and overexpression was defined as moderate to strong positivity. The prognostic impact was assessed by correlating protein expression with patient survival. The antitumoral effects of the dual DNMT1-G9a inhibitor CM272 were tested in PDAC cell lines, followed by transcriptomic analyses to identify underlying mechanisms. The in vivo antitumoral efficacy of CM272 was evaluated in PDAC xenograft and syngeneic mouse models, both alone and in combination with anti-PD1 immunotherapy.</p><p><strong>Results: </strong>DNMT1, G9a, and UHRF1 were significantly overexpressed in PDAC cells and stroma compared to normal pancreatic tissues. Simultaneous overexpression of the three proteins was associated with significantly reduced survival in resected PDAC patients. CM272 exhibited potent antiproliferative activity in PDAC cell lines, inducing apoptosis and altering key metabolic and cell cycle-related genes. CM272 also enhanced chemotherapy sensitivity and significantly inhibited tumor growth in vivo without detectable toxicity. Combination of CM272 with anti-PD1 therapy further improved antitumor responses and immune cell infiltration, particularly CD4 + and CD8 + T cells.</p><p><strong>Conclusions: </strong>The combined overexpression of DNMT1, G9a, and UHRF1 in PDAC is a strong predictor of poor prognosis. CM272, by targeting this epigenetic complex, shows promising therapeutic potential by inducing apoptosis, reprogramming metabolic pathways, and enhancing immune responses. The combination of CM272 with immunotherapy offers a novel, effective treatment strategy for PDAC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"13"},"PeriodicalIF":11.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984759","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":"AGD1/USP10/METTL13 complexes enhance cancer stem cells proliferation and diminish the therapeutic effect of docetaxel via CD44 m6A modification in castration resistant prostate cancer.","authors":"Hong Wang, Chunli Cui, Weiyi Li, Hui Wu, Jianjun Sha, Jiahua Pan, Wei Xue","doi":"10.1186/s13046-025-03272-3","DOIUrl":"10.1186/s13046-025-03272-3","url":null,"abstract":"<p><strong>Background: </strong>Most patients with prostate cancer inevitably progress to castration-resistant prostate cancer (CRPC), at which stage chemotherapeutics like docetaxel become the first-line treatment. However, chemotherapy resistance typically develops after an initial period of therapeutic efficacy. Increasing evidence indicates that cancer stem cells confer chemotherapy resistance via exosomes. This study demonstrated that AGD1, derived from prostate cancer stem cells (PCSCs), enhanced the stemness of prostate cancer cells and reduced the therapeutic effect of docetaxel in CRPC.</p><p><strong>Methods: </strong>Quantitative real-time PCR (qPCR) was employed to determine the expression levels of AGD1 and METTL13 mRNAs in PCSCs and exosomes. Protein expression levels were examined using western blots and dot blots. The potential functions of AGD1 and METTL13 in CRPC were investigated through cell proliferation assay, Transwell assay, EdU incorporation assays, Annexin V-FITC/PI staining, and sphere formation assays. To uncover the underlying mechanisms of AGD1, RNA pull-down assay, RIP, co-Immunoprecipitation (co-IP), mass spectrometry (MS), Methylated RNA immunoprecipitation (MeRIP) and single-base elongation and ligation-based qPCR amplification method (SELECT) were performed. The effects of AGD1 and METTL13 on CRPC development and metastasis under docetaxel treatment were analyzed using a xenograft mouse model and an organoid model. Additionally, liposomal-chitosan nanocomplex drug delivery systems were designed to explore AGD1's role in regulating docetaxel treatment resistance in CRPC.</p><p><strong>Results: </strong>AGD1 expression was upregulated in PCSCs and exosomes. Downregulating AGD1 enhanced the sensitivity of CRPC to docetaxel treatment by inhibiting their stemness, with the reverse also being true. RNA pull-down, combined with MS, co-IP and RIP assays, demonstrated that AGD1 binds to METTL13 and USP10, forming a complex that facilitates METTL13 protein accumulation through USP10-induced deubiquitination. MeRIP assay and SELECT assay revealed that METTL13 transcriptionally controls the mRNA decay of CD44 via m6A methylation. Additionally, this process activates the pSTAT3/PI3K-AKT signaling pathway. Organoid models and liposomal-chitosan nanocomplex drug delivery systems showed that reducing AGD1 expression enhanced the therapeutic effect of docetaxel in CRPC.</p><p><strong>Conclusions: </strong>AGD1 mediates the stemness and apoptosis of PCSCs and promotes docetaxel treatment resistance by enhancing tumor growth and metastasis through USP10/METTL13-mediated CD44 mRNA decay in CRPC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"12"},"PeriodicalIF":11.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980048","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":"PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands.","authors":"Vasudha Mishra, Alka Singh, Michael Korzinkin, Xiangying Cheng, Claudia Wing, Viktoria Sarkisova, Ashwin L Koppayi, Alexandra Pogorelskaya, Oksana Glushchenko, Manu Sundaresan, Venkat Thodima, Jack Carter, Koichi Ito, Peggy Scherle, Anna Trzcinska, Ivan Ozerov, Everett E Vokes, Grayson Cole, Frank W Pun, Le Shen, Yuxuan Miao, Alexander T Pearson, Mark W Lingen, Bruce Ruggeri, Ari J Rosenberg, Alex Zhavoronkov, Nishant Agrawal, Evgeny Izumchenko","doi":"10.1186/s13046-024-03270-x","DOIUrl":"10.1186/s13046-024-03270-x","url":null,"abstract":"<p><strong>Background: </strong>Adenoid cystic carcinoma (ACC) is a rare glandular malignancy, commonly originating in salivary glands of the head and neck. Given its protracted growth, ACC is usually diagnosed in advanced stage. Treatment of ACC is limited to surgery and/or adjuvant radiotherapy, which often fails to prevent disease recurrence, and no FDA-approved targeted therapies are currently available. As such, identification of new therapeutic targets specific to ACC is crucial for improved patients' outcomes.</p><p><strong>Methods: </strong>After thoroughly evaluating the gene expression and signaling patterns characterizing ACC, we applied PandaOmics (an AI-driven software platform for novel therapeutic target discovery) on the unique transcriptomic dataset of 87 primary ACCs. Identifying protein arginine methyl transferase 5 (PRMT5) as a putative candidate with the top-scored druggability, we next determined the applicability of PRMT5 inhibitors (PRT543 and PRT811) using ACC cell lines, organoids, and patient derived xenograft (PDX) models. Molecular changes associated with response to PRMT5 inhibition and anti-proliferative effect of the combination therapy with lenvatinib was then analyzed.</p><p><strong>Results: </strong>Using a comprehensive AI-powered engine for target identification, PRMT5 was predicted among potential therapeutic target candidates for ACC. Here we show that monotherapy with selective PRMT5 inhibitors induced a potent anti-tumor activity across several cellular and animal models of ACC, which was paralleled by downregulation of genes associated with ACC tumorigenesis, including MYB and MYC (the recognized drivers of ACC progression). Furthermore, as a subset of genes targeted by lenvatinib is upregulated in ACC, we demonstrate that addition of lenvatinib enhanced the growth inhibitory effect of PRMT5 blockade in vitro, suggesting a potential clinical benefit for patients expressing lenvatinib favorable molecular profile.</p><p><strong>Conclusion: </strong>Taken together, our study underscores the role of PRMT5 in ACC oncogenesis and provides a strong rationale for the clinical development of PRMT5 inhibitors as a targeted monotherapy or combination therapy for treatment of patients with this rare disease, based on the analysis of their underlying molecular profile.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"11"},"PeriodicalIF":11.4,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967194","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":"ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress.","authors":"Jenna L Carter, Yongwei Su, Eman T Al-Antary, Jianlei Zhao, Xinan Qiao, Guan Wang, Holly Edwards, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Steven A Buck, Maik Hüttemann, Joshua E Allen, Varun V Prabhu, Jay Yang, Jeffrey W Taub, Yubin Ge","doi":"10.1186/s13046-024-03267-6","DOIUrl":"10.1186/s13046-024-03267-6","url":null,"abstract":"<p><strong>Background: </strong>Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction. We previously reported that ONC213 disrupts oxidative phosphorylation and decreases Mcl-1 protein, which play a key role in venetoclax resistance. Here we investigated the antileukemic activity and underlying molecular mechanism of the combination of ONC213 + venetoclax against AML cells.</p><p><strong>Methods: </strong>Flow cytometry was used to determine drug-induced apoptosis. Protein level changes were determined by western blot. An AML cell line-derived xenograft mouse model was used to determine the effects of ONC213 + venetoclax on survival. A patient-derived xenograft (PDX) mouse model was used to determine drug effects on CD45+/CD34+/CD38-/CD123 + cells. Colony formation assays were used to assess drug effects on AML progenitor cells. Mcl-1 and Bax/Bak knockdown and Mcl-1 overexpression were used to confirm their role in the mechanism of action. The effect of ONC213 + venetoclax on mitochondrial respiration was determined using a Seahorse bioanalyzer.</p><p><strong>Results: </strong>ONC213 + venetoclax synergistically kills AML cells, including those resistant to venetoclax alone as well as venetoclax + azacitidine. The combination significantly reduced colony formation capacity of primary AML progenitors compared to the control and either treatment alone. Further, the combination prolonged survival in an AML cell line-derived xenograft model and significantly decreased LSCs in an AML PDX model.</p><p><strong>Conclusions: </strong>ONC213 can resensitize VEN + AZA-resistant AML cells to venetoclax therapy and target LSCs ex vivo and in vivo.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"10"},"PeriodicalIF":11.4,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11714820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958200","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":"Phenotypic diversity of CTCs and tdEVs in liquid biopsies of tumour-draining veins is linked to poor prognosis in colorectal cancer.","authors":"Stefan A Cieslik, Andrés G Zafra, Christiane Driemel, Monica Sudarsanam, Jan-Philipp Cieslik, Georg Flügen, Levent Dizdar, Andreas Krieg, Sascha Vaghiri, Hany Ashmawy, Stephen Fung, Miriam Wilms, Leon W M M Terstappen, Afroditi Nanou, Hans Neubauer, Nuh N Rahbari, Wolfram T Knoefel, Nikolas H Stoecklein, Rui P L Neves","doi":"10.1186/s13046-024-03259-6","DOIUrl":"https://doi.org/10.1186/s13046-024-03259-6","url":null,"abstract":"<p><strong>Background: </strong>Circulating tumour cells (CTCs) and tumour-derived extracellular vesicles (tdEVs) have great potential for monitoring therapy response and early detection of tumour relapse, facilitating personalized adjuvant therapeutic strategies. However, their low abundance in peripheral blood limits their informative value. In this study, we explored the presence of CTCs and tdEVs collected intraoperatively from a tumour-draining vein (DV) and via a central venous catheter (CVC) prior to tumour resection.</p><p><strong>Methods: </strong>CellSearch analyses of 395 blood samples from 306 patients with gastrointestinal tumours and 93 blood samples from healthy donors were used to establish and validate gates for the automated detection of CTCs and tdEVs with ACCEPT software and R scripts. The selected gate settings were applied to 227 samples of 142 patients with colorectal cancer (CRC) from two independent collectives. Phenotypic features were obtained via numeric analysis of their fluorescence signals (e.g. size, shape, and intensity) and were used for calculating diversity using Shannon index (SI) of clusters generated via the k-means algorithm after Uniform Manifold Approximation and Projection (UMAP) pre-processing, and standard deviation (SD).</p><p><strong>Results: </strong>CTCs and tdEVs were more abundant in the DV samples compared to CVC samples (p < 0.05). tdEVs were detected in higher numbers than CTCs in both compartments. Importantly, tdEVs in CVCs were associated with tumor spread, whereas CTCs in DVs were linked to tumor size. In both compartments, the prognostic value of tdEVs for overall survival (OS) surpassed that of CTCs, as demonstrated by univariate, multivariate, and Kaplan-Meier analyses. CTCs and tdEVs in DVs were phenotypically distinct, being larger, more eccentric, and displaying stronger cytokeratin intensities (p < 0.05) compared to those in CVC samples. Furthermore, increased diversity in CTC and tdEV phenotypes was significantly associated with shorter survival, validating the prognostic relevance of the SD-diversity metric.</p><p><strong>Conclusion: </strong>Our study demonstrates that DV sampling significantly enhances the detection of prognostically relevant CTCs and tdEVs in CRC patients, underscoring the superior prognostic significance of tdEVs compared to CTCs. Importantly, the combined phenotypic diversity of both markers emerges as a more powerful biomarker than their enumeration alone. These findings suggest that comprehensive, automated analysis of CTCs and tdEVs in DVs may open new avenues for tailoring individualized therapies in CRC patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"9"},"PeriodicalIF":11.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11708080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958202","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":"Periostin-mediated NOTCH1 activation between tumor cells and HSCs crosstalk promotes liver metastasis of small cell lung cancer.","authors":"Linlin Lou, Keren Peng, Shumin Ouyang, Wen Ding, Jianshan Mo, Jiayu Yan, Xiaoxiao Gong, Guopin Liu, Jinjian Lu, Peibin Yue, Kai Zhang, Jian Zhang, Yan-Dong Wang, Xiao-Lei Zhang","doi":"10.1186/s13046-024-03266-7","DOIUrl":"https://doi.org/10.1186/s13046-024-03266-7","url":null,"abstract":"<p><strong>Background: </strong>Metastasis is the primary cause of mortality in small cell lung cancer (SCLC), with the liver being a predominant site for distal metastasis. Despite this clinical significance, mechanisms underlying the interaction between SCLC and liver microenvironment, fostering metastasis, remain unclear.</p><p><strong>Methods: </strong>SCLC patient tissue array, bioinformatics analysis were performed to demonstrate the role of periostin (POSTN) in SCLC progression, metastasis, and prognosis. Cell migration, invasion and sphere formation assay were performed to determine the oncogenic role of POSTN. RNA sequencing analysis was utilized to identify the key signaling pathway regulated by POSTN. Immunoprecipitation, immunofluorescence and co-culture system were used to clarify the mechanism of POSTN-NOTCH1 axis in tumor cells-hepatic stellate cells (HSCs) crosstalk. Subcutaneous xenograft model and liver metastasis model were established to examine the anti-tumor growth and metastases effect of targeting POSTN-NOTCH1 signaling axis.</p><p><strong>Results: </strong>Elevated expression of POSTN in SCLC is correlated with accelerated tumor progression and metastasis. Conditioned medium rich in POSTN derived from SCLC tumors demonstrates the ability to activate HSCs in the liver microenvironment. Mechanistically, POSTN emerges as a binding partner for the membrane receptor NOTCH1 and transducing the extracellular signals to intracellular fibroblasts. Furthermore, targeting the POSTN-NOTCH1 signaling axis proves effective in suppressing SCLC tumor growth and inhibiting liver metastasis. This study elucidates that the SCLC-derived secreted protein POSTN interacts with NOTCH1 on HSCs to promote the activation of HSCs, thereby providing a favorable microenvironment for liver metastasis.</p><p><strong>Conclusion: </strong>These findings uncover the intricate communications between primary SCLC cells and HSCs in the tumor microenvironment mediated by the secreted protein POSTN in the context of liver metastasis. Consequently, targeting the POSTN-NOTCH1 signaling axis emerges as a promising therapeutic strategy for metastatic SCLC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"6"},"PeriodicalIF":11.4,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958201","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":"hnRNPU-mediated pathogenic alternative splicing drives gastric cancer progression.","authors":"Guoguo Jin, Yanming Song, Shaobo Fang, Mingyang Yan, Zhaojie Yang, Yang Shao, Kexin Zhao, Meng Liu, Zhenwei Wang, Zhiping Guo, Zigang Dong","doi":"10.1186/s13046-024-03264-9","DOIUrl":"https://doi.org/10.1186/s13046-024-03264-9","url":null,"abstract":"<p><strong>Background: </strong>Alternative splicing (AS) is a process that facilitates the differential inclusion of exonic sequences from precursor messenger RNAs, significantly enhancing the diversity of the transcriptome and proteome. In cancer, pathogenic AS events are closely related to cancer progression. This study aims to investigate the role and regulatory mechanisms of AS in gastric cancer (GC).</p><p><strong>Methods: </strong>We analyzed AS events in various tumor samples and identified hnRNPU as a key splicing factor in GC. The effects of hnRNPU on cancer progression were assessed through in vitro and in vivo experiments. Gene knockout models and the FTO inhibitor (meclofenamic acid) were used to validate the interaction between hnRNPU and FTO and their impact on AS.</p><p><strong>Results: </strong>We found that hnRNPU serves as a key splicing factor in GC, and its high expression is associated with poor clinical prognosis. Genetic depletion of hnRNPU significantly reduced GC progression. Mechanistically, the m⁶A demethylase FTO interacts with hnRNPU transcripts, decreasing the m⁶A modification levels of hnRNPU, which leads to exon 14 skipping of the MET gene, thereby promoting GC progression. The FTO inhibitor meclofenamic acid effectively inhibited GC cell growth both in vitro and in vivo.</p><p><strong>Conclusion: </strong>The FTO/hnRNPU axis induces aberrant exon skipping of MET, thereby promoting GC cell growth. Targeting the FTO/hnRNPU axis may interfere with abnormal AS events and provide a potential diagnostic and therapeutic strategy for GC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"8"},"PeriodicalIF":11.4,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958069","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":"Antibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice.","authors":"Carmine Carbone, Roberto De Luca, Emanuele Puca, Antonio Agostini, Alessia Caggiano, Lorenzo Priori, Annachiara Esposito, Serena Ascrizzi, Geny Piro, Lisa Salvatore, Francesco De Sanctis, Stefano Ugel, Vincenzo Corbo, Dario Neri, Giampaolo Tortora","doi":"10.1186/s13046-024-03238-x","DOIUrl":"https://doi.org/10.1186/s13046-024-03238-x","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly type of cancer, with an extremely low five-year overall survival rate. To date, current treatment options primarily involve various chemotherapies, which often prove ineffective and are associated with substantial toxicity. Furthermore, immunotherapies utilizing checkpoint inhibitors have shown limited efficacy in this context, highlighting an urgent need for novel therapeutic strategies. This study investigates the preclinical efficacy of an innovative targeted therapy based on antibody-cytokine fusion proteins, specifically interleukin-2 (IL-2), a pivotal driver of cell-mediated immunity, fused to L19 antibody, which selectively binds to extra domain B of fibronectin (EDB-FN1) expressed in the tumor microenvironment.</p><p><strong>Methods: </strong>We tested the effectiveness of different immunocytokines through in vivo characterization in syngeneic C57BL/6J orthotopic mouse models of PDAC. Based on these results, we decided to focus on L19-IL2. To assess the efficacy of this immunocytokine we developed an ex-vivo immune-spheroid interaction platform derived from murine 3D pancreatic cultures, and telomerase reverse transcriptase (TERT) specific T-lymphocytes. Moreover, we evaluated the anti-cancer effect of L19-IL2 in combination with standard therapy in vivo experiments in PDAC mouse models. Tumor samples collected after the treatments were characterized for tumor infiltrating immune cell components by bulk RNA sequencing (RNA-seq) and spatial transcriptomics (Stereo-seq) analysis.</p><p><strong>Results: </strong>The tumor-targeted L19-IL2 fusion protein demonstrated potent, dose-dependent anti-tumor activity in mice with pancreatic tumors resistant to standard chemotherapy. Spatial Transcriptomics (ST) and RNA-seq analyses indicated that L19-IL2 treatment induced a significant influx of immune cells into the tumor microenvironment, with these cells expressing activation markers like granzymes, perforins, and the IL-2 receptors.</p><p><strong>Conclusions: </strong>Our results demonstrated that L19-IL2 enhances immune infiltration and cytotoxicity, remodeling the \"cold\" tumor microenvironment (TME) in PDAC. This innovative antibody-cytokine fusion protein improves therapeutic outcomes, paving the way for novel targeted treatment strategies in PDAC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"7"},"PeriodicalIF":11.4,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958148","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}