Journal of Experimental & Clinical Cancer Research最新文献

{"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":"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":"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":"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}

{"title":"Correction: IFI6 depletion inhibits esophageal squamous cell carcinoma progression through reactive oxygen species accumulation via mitochondrial dysfunction and endoplasmic reticulum stress.","authors":"Zhenchuan Liu, Shaorui Gu, Tiancheng Lu, Kaiqing Wu, Lei Li, Chenglai Dong, Yongxin Zhou","doi":"10.1186/s13046-024-03256-9","DOIUrl":"10.1186/s13046-024-03256-9","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"5"},"PeriodicalIF":11.4,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation.","authors":"Yi Zhang, Qin-Shan Li, Hong-Lin Liu, Hong-Ting Tang, Han-Lin Yang, Dao-Qiu Wu, Yu-Ying Huang, Li-Cheng Li, Li-Hong Liu, Meng-Xing Li","doi":"10.1186/s13046-024-03265-8","DOIUrl":"10.1186/s13046-024-03265-8","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"4"},"PeriodicalIF":11.4,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928551","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":"CYP3A5 promotes glioblastoma stemness and chemoresistance through fine-tuning NAD⁺/NADH ratio.","authors":"Wentao Hu, Xiaoteng Cui, Hongyu Liu, Ze Li, Xu Chen, Qixue Wang, Guolu Zhang, Er Wen, Jinxin Lan, Junyi Chen, Jialin Liu, Chunsheng Kang, Ling Chen","doi":"10.1186/s13046-024-03254-x","DOIUrl":"https://doi.org/10.1186/s13046-024-03254-x","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma multiforme (GBM) exhibits a cellular hierarchy with a subpopulation of stem-like cells known as glioblastoma stem cells (GSCs) that drive tumor growth and contribute to treatment resistance. NAD(H) emerges as a crucial factor influencing GSC maintenance through its involvement in diverse biological processes, including mitochondrial fitness and DNA damage repair. However, how GSCs leverage metabolic adaptation to obtain survival advantage remains elusive.</p><p><strong>Methods: </strong>A multi-step process of machine learning algorithms was implemented to construct the glioma stemness-related score (GScore). Further in silico and patient tissue analyses validated the predictive ability of the GScore and identified a potential target, CYP3A5. Loss-of-function or gain-of-function genetic experiments were performed to assess the impact of CYP3A5 on the self-renewal and chemoresistance of GSCs both in vitro and in vivo. Mechanistic studies were conducted using nontargeted metabolomics, RNA-seq, seahorse, transmission electron microscopy, immunofluorescence, flow cytometry, ChIP‒qPCR, RT‒qPCR, western blotting, etc. The efficacy of pharmacological inhibitors of CYP3A5 was assessed in vivo.</p><p><strong>Results: </strong>Based on the proposed GScore, we identify a GSC target CYP3A5, which is highly expressed in GSCs and temozolomide (TMZ)-resistant GBM patients. This elevated expression of CYP3A5 is attributed to transcription factor STAT3 activated by EGFR signaling or TMZ treatment. Depletion of CYP3A5 impairs self-renewal and TMZ resistance of GSCs. Mechanistically, CYP3A5 maintains mitochondrial fitness to promote GSC metabolic adaption through the NAD⁺/NADH-SIRT1-PGC1α axis. Additionally, CYP3A5 enhances the activity of NAD-dependent enzyme PARP to augment DNA damage repair. Treatment with CYP3A5 inhibitor alone or together with TMZ effectively suppresses tumor growth in vivo.</p><p><strong>Conclusion: </strong>Together, this study suggests that GSCs activate STAT3 to upregulate CYP3A5 to fine-tune NAD⁺/NADH for the enhancement of mitochondrial functions and DNA damage repair, thereby fueling tumor stemness and conferring TMZ resistance, respectively. Thus, CYP3A5 represents a promising target for GBM treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"3"},"PeriodicalIF":11.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928552","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":"Gastric cancer-derived exosomal let-7 g-5p mediated by SERPINE1 promotes macrophage M2 polarization and gastric cancer progression.","authors":"Zhenzhen Ye, Jianfeng Yi, Xiangyan Jiang, Wengui Shi, Hao Xu, Hongtai Cao, Long Qin, Lixin Liu, Tianming Wang, Zhijian Ma, Zuoyi Jiao","doi":"10.1186/s13046-024-03269-4","DOIUrl":"10.1186/s13046-024-03269-4","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated macrophages (TAMs), particularly M2-polarized TAMs, are significant contributors to tumor progression, immune evasion, and therapy resistance in gastric cancer (GC). Despite efforts to target TAM recruitment or depletion, clinical efficacy remains limited. Consequently, the identification of targets that specifically inhibit or reprogram M2-polarized TAMs presents a promising therapeutic strategy.</p><p><strong>Objective: </strong>This study aims to identify a dual-function target in GC cells that drives both malignant phenotypes and M2 macrophage polarization, revealing its molecular mechanisms to provide novel therapeutic targets for selectivly targeting M2-polarized TAMs in GC.</p><p><strong>Methods: </strong>Transcriptomic and clinical data from GC and adjacent tissues were utilized to identify mRNAs associated with high M2 macrophage infiltration and poor prognosis. Single-cell sequencing elucidated cell types expressing the target gene. Transwell co-culture and exosome intervention experiments demonstrated its role in M2 polarization. Small RNA sequencing of exosomes, western blotting, and CoIP assays revealed the molecular mechanisms underlying exosome-mediated M2 polarization. Protein array, ChIP and dual-luciferase reporter assays clarified the molecular mechanisms by which the target gene regulated exosomal miRNA. In vivo validation was performed using xenograft tumor models.</p><p><strong>Results: </strong>SERPINE1 was identified as a highly expressed mRNA in GC tissues and cells, significantly associated with advanced clinical stages, worse prognosis, and higher M2 macrophage infiltration in patients with GC. SERPINE1 overexpression in GC cells promoted tumor growth and M2 macrophage polarization. SERPINE1 facilitated the transfer of let-7 g-5p to macrophages via cancer-derived exosomes, inducing M2 polarization. Exosomal let-7 g-5p internalized by macrophages downregulated SOCS7 protein levels, disrupting its interaction with STAT3 and relieving the inhibition of STAT3 phosphorylation, thereby leading to STAT3 hyperactivation, which consequently drove M2 polarization. Additionally, in GC cells, elevated SERPINE1 expression activated JAK2, enhancing STAT3 binding to the let-7 g-5p promoter and promoting its transcription, thereby increasing let-7 g-5p levels in exosomes.</p><p><strong>Conclusion: </strong>GC cell-derived SERPINE1, functioning as a primary driver of GC growth and TAM M2 polarization, promotes M2 polarization through the regulation of exosomal let-7 g-5p transfer via autocrine activation of the JAK2/STAT3 signaling pathway. These findings elucidate a novel mechanism of SERPINE1-induced M2 polarization and highlight SERPINE1 as a promising target for advancing immunotherapy and targeted treatments in GC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"2"},"PeriodicalIF":11.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923555","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":"Specifically blocking αvβ8-mediated TGF-β signaling to reverse immunosuppression by modulating macrophage polarization.","authors":"Cuicui Guo, Hui Sun, Yulei Du, Xiaodong Dai, Yu Pang, Zhen Han, Xinhui Xiong, Shaowei Li, Junhua Zhang, Qingbing Zheng, Xun Gui","doi":"10.1186/s13046-024-03250-1","DOIUrl":"10.1186/s13046-024-03250-1","url":null,"abstract":"<p><strong>Background: </strong>Targeting the TGF-β pathway in tumor therapy has proven challenging due to the highly context-dependent functions of TGF-β. Integrin αvβ8, a pivotal activator of TGF-β, has been implicated in TGF-β signaling within tumors, as demonstrated by the significant anti-tumor effects of anti-αvβ8 antibodies. Nevertheless, the expression profile of αvβ8 remains a subject of debate, and the precise mechanisms underlying the anti-tumor effects of anti-αvβ8 antibodies are not yet fully elucidated.</p><p><strong>Methods: </strong>We utilized single-cell RNA sequencing to assess αvβ8 expression across various human tumors. An anti-αvβ8 antibody was developed and characterized for its binding and blocking properties in vitro. Cryo-EM single-particle analysis was employed to study the detailed interaction between αvβ8 and the antibody Fab fragment. The anti-tumor efficacy of the antibody was evaluated in syngeneic mouse models with varying levels of αvβ8 expression, both as a monotherapy and in combination with PD-1 antibodies. Human PBMCs were isolated to investigate αvβ8 expression in myeloid cells, and macrophages were exposed to the antibody to study its impact on macrophage polarization. Pharmacokinetic studies of the αvβ8 antibody were conducted in cynomolgus monkeys.</p><p><strong>Results: </strong>Integrin αvβ8 is notably expressed in certain tumor types and tumor-infiltrating macrophages. The specific αvβ8 antibody 130H2 demonstrated high affinity, specificity, and blocking potency in vitro. Cryo-EM analysis further revealed that 130H2 interacts exclusively with the β8 subunit, without binding to the αv subunit. In vivo studies showed that this antibody significantly inhibited tumor growth and alleviated immunosuppression by promoting immune cell infiltration. Furthermore, combining the antibody with PD-1 inhibition produced a synergistic anti-tumor effect. In human PBMCs, monocytes exhibited high αvβ8 expression, and the antibody directly modulated macrophage polarization. Tumors with elevated αvβ8 expression were particularly responsive to 130H2 treatment. Additionally, favorable pharmacokinetic properties were observed in cynomolgus monkeys.</p><p><strong>Conclusions: </strong>In summary, integrin αvβ8 is highly expressed in certain tumors and tumor-infiltrating macrophages. Targeting αvβ8 with a blocking antibody significantly inhibits tumor growth by modulating macrophage polarization and enhancing immune cell infiltration. Combining αvβ8 targeting with PD-1 treatment markedly increases the sensitivity of immune-excluded tumors. These results support further clinical evaluation of αvβ8 antibodies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"1"},"PeriodicalIF":11.4,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916267","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}