Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Are monocytes a preferable option to develop myeloid cell-based therapies for solid tumors?","authors":"Daisy Bhatia, Riccardo Dolcetti, Roberta Mazzieri","doi":"10.1186/s13046-025-03359-x","DOIUrl":"10.1186/s13046-025-03359-x","url":null,"abstract":"<p><p>In the last two decades, novel and promising cell-based therapies have populated the treatment landscape for haematological tumors. However, commonly exploited T and NK cell-based therapies show limited applicability to solid tumors. This is mainly given by the impaired tumor trafficking capability and limited effector activity of these cells within a highly immunosuppressive tumor microenvironment. Myeloid cells spontaneously home to tumors and can thus be reprogrammed and/or engineered to directly attack tumor cells or locally and selectively deliver therapeutically relevant payloads that may improve the efficacy of immunotherapy against difficult-to-access solid tumors. In the context of myeloid cell-based therapies, adoptive transfer of monocytes has often been overshadowed by infusion of differentiated macrophages or hematopoietic stem cell transplantation despite their promising therapeutic potential. Here, we summarize the recent improvements and benefits of using monocytes for the treatment of solid tumors, their current clinical applications and the challenges of their use as well as some possible strategies to overcome them.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"98"},"PeriodicalIF":11.4,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Viral expression of NE/PPE enhances anti-colorectal cancer efficacy of oncolytic adenovirus by promoting TAM M1 polarization to reverse insufficient effector memory/effector CD8⁺ T cell infiltration.","authors":"Shuo Wang, Lingkai Kong, Linpei Wang, Yan Zhuang, Ciliang Guo, Yuxin Zhang, Huawei Cui, Xiaosong Gu, Junhua Wu, Chunping Jiang","doi":"10.1186/s13046-025-03358-y","DOIUrl":"10.1186/s13046-025-03358-y","url":null,"abstract":"<p><strong>Background: </strong>Oncolytic adenoviruses are among the most widely utilized oncolytic viruses due to their notable anti-tumor and gene expression capabilities, and modification of ADVs to create armed adenoviruses remains a popular research direction. Nonetheless, immune suppression triggered by ADV and targeted enhancements based on this limitation have been relatively unexplored.</p><p><strong>Methods: </strong>Flow cytometry was employed to assess immune infiltration in the tumor microenvironment following ADV therapy. Targeted novel recombinant oncolytic viruses, ADV^NE and ADV^PPE, were designed, and their antitumor efficacy, safety, and ability to reshape immune infiltration were evaluated in both subcutaneous tumor models in mice and in vitro experiments. Immune cell depletion assays confirmed the critical role of macrophages. The impact of HMGB1 on macrophage polarization was investigated using shRNA, qRT-PCR, ELISA, and flow cytometry. Furthermore, the importance of TLR4 and its downstream pathways was validated through immunoprecipitation, Western blotting, homozygous knockout mice, and TLR4 inhibitors.</p><p><strong>Results: </strong>We demonstrated that ADV limits the infiltration of effector memory/effector CD8 + T cells (T_EM/T_E) within the tumor microenvironment. To address this, we leveraged the strong capacity of NE or PPE to recruit T_EM/T_E by constructing novel recombinant oncolytic adenoviruses, ADV^NE or ADV^PPE, armed with NE or PPE. These recombinant viruses induce pyroptosis in colorectal cancer cells accompanied by the release of HMGB1. HMGB1 binds to TLR4 on the surface of macrophages, activating the MyD88-NFκB-NLRP3 (ASC) pathway and promoting M1 polarization of TAMs, thereby increasing T_EM/T_E cell infiltration and enhancing antitumor efficacy.</p><p><strong>Conclusions: </strong>In summary, this study presents the development of the novel oncolytic adenoviruses ADV^NE and ADV^PPE with enhanced anti-tumor efficacy and provides an in-depth exploration of their specific anti-tumor mechanisms. These findings indicate promising clinical therapeutic prospects and offer new insights for advancing oncolytic adenovirus therapies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"97"},"PeriodicalIF":11.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-1297 is frequently downmodulated in flat epithelial atypia of the breast and promotes mammary neoplastic transformation via EphrinA2 regulation.","authors":"Giorgia Scafetta, Gian Luca Rampioni Vinciguerra, Simona Giglio, Omar Faruq, Roberto Cirombella, Ilenia Segatto, Francesca Citron, Maria Chiara Mattevi, Elisabetta Di Renzi, Luciano Cascione, Pierluigi Gasparini, Barbara Belletti, Gustavo Baldassarre, Andrea Sacconi, Giovanni Blandino, Andrea Vecchione","doi":"10.1186/s13046-025-03354-2","DOIUrl":"10.1186/s13046-025-03354-2","url":null,"abstract":"<p><p>Breast cancer ranks as the most prevalent form of cancer globally. Currently, advanced screening methods have significantly improved early detection rates. These achievements have led to more non-invasive cancer diagnoses and underscored the clinical relevance of precursor lesions like flat epithelial atypia (FEA), a histological condition characterized by mild atypical changes in the normal epithelium lining the mammary ducts. Despite the increasing detection of FEA in mammary biopsy, our understanding of the biological behavior of this entity remains limited and, as a consequence, the clinical management of patients is still being debated. Evidence from the literature indicates that dysregulation of microRNAs contributes to all stages of breast cancer progression, potentially serving as valuable markers of disease evolution. In this study, through a comparison of the microRNA profiles of normal mammary epithelium, FEA, and non-invasive breast cancer in three cohorts of patients, we identified downregulation of miR-1297 as a common feature in both FEA and non-invasive breast cancer compared to the normal counterpart. Mechanistically, overexpression of miR-1297 inhibits the growth of breast cancer cells by targeting the oncogenic receptor tyrosine kinase EphrinA2. In contrast, downregulation of miR-1297 increases proliferation and alters the morphology of normal mammary epithelial cells in a three-dimensional context. These findings pinpoint the downregulation of miR-1297 as an early event in mammary transformation and suggest its potential role as a driver of progression in FEA, harboring the capacity to evolve into malignancy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"96"},"PeriodicalIF":11.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RBM10 deficiency promotes brain metastasis by modulating sphingolipid metabolism in a BBB model of EGFR mutant lung adenocarcinoma.","authors":"Gang Xu, Bo An, Ruqiong Wang, Bo Pan, Huiting Hao, Xingmei Ren, Zihan Jing, Weitong Gao, Yajie Li, Yan Jin, Enguang Lin, Lihua Shang, Dexin Jia, Yan Yu","doi":"10.1186/s13046-025-03347-1","DOIUrl":"10.1186/s13046-025-03347-1","url":null,"abstract":"<p><strong>Background: </strong>Brain metastasis significantly contributes to the failure of targeted therapy in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (LUAD). Reduced expression of RNA-binding motif protein 10 (RBM10) is associated with brain metastasis in these patients. However, the mechanism by which RBM10 affects brain metastasis in EGFR-mutated LUAD remains unclear.</p><p><strong>Methods: </strong>An in vitro blood-brain barrier (BBB) model and brain metastasis-prone cell lines (BrM3) were established to confirm the brain metastatic potential of tumor cells following RBM10 knockdown. The roles of RBM10 and galactosylceramidase (GALC) in LUAD brain metastases were analyzed using cellular phenotypic assays and molecular biology techniques, including the combined analysis of Nanopore sequencing and CLIP-seq, minigene assays, and others.</p><p><strong>Results: </strong>This study demonstrates that RBM10 plays a vital role in inhibiting brain metastasis from EGFR-mutated LUAD by modulating sphingolipid metabolism. When RBM10 expression is low, GALC enters the nucleus to function. RBM10 deficiency inhibits exon skipping during GALC splicing, leading to upregulated GALC expression and increased sphingosine 1-phosphate (S1P) synthesis. S1P enhances BBB permeability, thereby promoting brain metastasis. Additionally, animal experiments show that the targeted agents Fingolimod (an S1P inhibitor) and RU-SKI-43 (a potential drug for RBM10 mutation) suppress the growth of brain metastasis.</p><p><strong>Conclusion: </strong>This study offers insights into the potential mechanisms of brain metastasis in LUAD and suggests a possible therapeutic target for further investigation.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"95"},"PeriodicalIF":11.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607076","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":"Unveiling radiobiological traits and therapeutic responses of BRAF^V600E-mutant colorectal cancer via patient-derived organoids.","authors":"Peiyuan Mu, Shaobo Mo, Xingfeng He, Hui Zhang, Tao Lv, Ruone Xu, Luoxi He, Fan Xia, Shujuan Zhou, Yajie Chen, Yaqi Wang, Lijun Shen, Juefeng Wan, Lili Huang, Weiqing Lu, Xinyue Liang, Xiaomeng Li, Ping Lu, Junjie Peng, Guoqiang Hua, Kewen Hu, Zhen Zhang, Yan Wang","doi":"10.1186/s13046-025-03349-z","DOIUrl":"10.1186/s13046-025-03349-z","url":null,"abstract":"<p><strong>Background: </strong>Radiotherapy (RT) is an essential treatment for colorectal cancer (CRC), yet the factors influencing radiosensitivity remain unclear. In the quest to enhance the therapeutic efficacy in CRC, the interplay between genetic mutations and RT sensitivity has emerged as a pivotal yet enigmatic area.</p><p><strong>Methods: </strong>We harness the fidelity of patient-derived organoids (PDOs) to dissect the molecular landscape of radiosensitivity, with a particular emphasis on BRAF^V600E mutations. To further investigate, a cohort of 9 BRAF^V600E-mutant and 10 BRAF wild-type PDOs is constructed to systematically assess the radiobiological traits of BRAF^V600E-mutant CRC, including morphology, cell viability, and DNA damage, while also evaluating their responses to chemotherapy and chemoradiotherapy.</p><p><strong>Results: </strong>Our systematic investigation unveils a profound correlation between BRAF^V600E mutation status and radioresistance, which is validated by clinical treatment responses. Intriguingly, BRAF^V600E-mutant PDOs exhibit reduced sensitivity to conventional chemotherapy, yet demonstrate an enhanced response to combined chemoradiotherapy, characterized by increased apoptosis. The results are validated through in vivo analyses using patient-derived organoid xenograft mouse models and aligned with patient clinical outcomes.</p><p><strong>Conclusions: </strong>This study outlines the distinct radiobiological profile of BRAF^V600E-mutant CRC, underscoring the critical role of radiotherapy in comprehensive treatment strategies. This work not only advances our molecular understanding of CRC but also paves the way for precision medicine, offering valuable insights for therapeutic decision-making in the clinical management of BRAF^V600E-mutant CRC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"92"},"PeriodicalIF":11.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607080","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":"USP10/XAB2/ANXA2 axis promotes DNA damage repair to enhance chemoresistance to oxaliplatin in colorectal cancer.","authors":"Xingwu Liu, Shaoming Zhang, Yue An, Boyang Xu, Guanyu Yan, Mingjun Sun","doi":"10.1186/s13046-025-03357-z","DOIUrl":"10.1186/s13046-025-03357-z","url":null,"abstract":"<p><strong>Background: </strong>Oxaliplatin-based chemotherapy is the first-line treatment for colorectal cancer (CRC). However, oxaliplatin resistance remains a major challenge contributing to treatment failure and poor prognosis. An increased capacity for DNA damage repair is a key mechanism underlying oxaliplatin resistance. Although XPA binding protein 2 (XAB2) is implicated in various DNA damage repair mechanisms, its specific role in mediating oxaliplatin resistance remains unclear.</p><p><strong>Methods: </strong>XAB2 was identified through analysis of public datasets. Western blot analysis and immunohistochemistry were performed to evaluate XAB2 expression, while survival analysis was performed to assess its clinical significance in CRC. Functional experiments were then conducted to assess the impact of XAB2 on proliferation, DNA damage repair, and oxaliplatin resistance in CRC. RNA sequencing (RNA-seq) and Chromatin immunoprecipitation-sequencing (ChIP-seq) were used to identify XAB2 target genes. Co-immunoprecipitation (Co-IP) and mass spectrometry were used to identify the proteins interacting with XAB2. Dual-luciferase reporter assays, ChIP-qPCR, Co-IP, ubiquitination site mass spectrometry, and ubiquitin assays were used to analyse the interactions and potential mechanisms involving XAB2, Annexin A2 (ANXA2), and ubiquitin-specific protease 10 (USP10).</p><p><strong>Results: </strong>XAB2 was found to be expressed in CRC and was associated with poor prognosis in patients with CRC. XAB2 promoted CRC cell proliferation and enhanced oxaliplatin resistance by promoting DNA damage repair. Mechanistically, CRC cells treated with oxaliplatin exhibited increased USP10 nuclear expression. USP10 bound to XAB2 and deubiquitinated XAB2 K48-linked polyubiquitination at K593, thereby stabilising XAB2 by reducing its degradation via the ubiquitin-proteasome pathway. XAB2 upregulates ANXA2 expression at the transcriptional level by binding to the ANXA2 promoter, thereby promoting DNA damage repair, mitigating oxaliplatin-induced DNA damage, and enhancing oxaliplatin resistance.</p><p><strong>Conclusions: </strong>In summary, this study demonstrates that the USP10/XAB2/ANXA2 axis promotes proliferation, DNA damage repair, and oxaliplatin resistance in CRC. These findings uncover a novel mechanism of oxaliplatin resistance in CRC and suggest potential therapeutic targets for improving the efficacy of oxaliplatin in CRC treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"94"},"PeriodicalIF":11.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607081","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":"Single-cell transcriptomics analysis reveals that the tumor-infiltrating B cells determine the indolent fate of papillary thyroid carcinoma.","authors":"Chunmei Li, Pei Wang, Zhizhong Dong, Weihan Cao, Yanjun Su, Jianming Zhang, Shuyan Zhao, Zhiyuan Wang, Zi Lei, Li Shi, Ruochuan Cheng, Wen Liu","doi":"10.1186/s13046-025-03341-7","DOIUrl":"10.1186/s13046-025-03341-7","url":null,"abstract":"<p><strong>Objective: </strong>Active surveillance (AS) offers a viable alternative to surgical intervention for the management of indolent papillary thyroid carcinoma (PTC), helping to minimize the incidence of unnecessary treatment. However, the broader adoption of AS is hindered by the need for more reliable diagnostic markers. This study aimed to identify the differences between indolent and progressive PTC and find new targets for biomarker development and therapeutic strategies.</p><p><strong>Methods: </strong>We used single-cell RNA sequencing (scRNA-seq) to analyze cellular differences in 10 early-stage PTC tumors. Findings were validated in an additional 25 tumors using cell co-culture, migration assays, immunofluorescence staining, flow cytometry, and analysis of data from The Cancer Genome Atlas (TCGA).</p><p><strong>Results: </strong>Tumor-infiltrating B cells (TIL-B), particularly germinal center B cells (GC-B), were more abundant in indolent PTC. These cells suppressed thyroid cell proliferation in both indolent and progressive cases, though indolent PTC had a higher capacity to recruit peripheral B cells. In indolent cases, TIL-B cells showed increased proliferation and formed clusters within tertiary lymphoid structures (TLS). PTPRC-CD22 interactions were identified as potential drivers of TIL-B cell proliferation. Markers linked to GC-B cells, such as LMO2, were highlighted as potential diagnostic and prognostic indicators for indolent PTC.</p><p><strong>Conclusion: </strong>This study provides insights into the cellular landscape of early-stage PTC, revealing distinct tumor and immune microenvironment features in indolent and progressive cases. These findings advance the understanding of indolent PTC biology and support the development of reliable diagnostic and prognostic biomarkers.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"91"},"PeriodicalIF":11.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607077","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":"CRSP8-driven fatty acid metabolism reprogramming enhances hepatocellular carcinoma progression by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.","authors":"Yuxi Lin, Zhixing Liang, Zhiyan Weng, Xiaofang Liu, Feng Zhang, Yutian Chong","doi":"10.1186/s13046-025-03329-3","DOIUrl":"10.1186/s13046-025-03329-3","url":null,"abstract":"<p><strong>Background: </strong>In-depth exploration into the dysregulation of lipid metabolism in hepatocellular carcinoma (HCC) has contributed to the development of advanced antitumor strategies. CRSP8 is a critical component of mediator multiprotein complex involved in transcriptional recruiting. However, the regulatory mechanisms of CRSP8 on fatty acid metabolism reprogramming and HCC progression remain unclear.</p><p><strong>Methods: </strong>In-silico/house dataset analysis, lipid droplets (LDs) formation, HCC mouse models and targeted lipidomic analysis were performed to determine the function of CRSP8 on regulating lipid metabolism in HCC. The subcellular colocalization and live cell imaging of LDs, transmission electron microscopy, co-immunoprecipitation and luciferase reporter assay were employed to investigate their potential mechanism.</p><p><strong>Results: </strong>CRSP8 was identified as a highly expressed oncogene essential for the proliferation and aggressiveness of HCC in vitro and in vivo. The tumor promotion of CRSP8 was accompanied by LDs accumulation and increased de novo fatty acids (FAs) synthesis. Moreover, CRSP8 diminished the colocalization between LC3 and LDs to impair lipophagy in a nuclear-localized PPARα-dependent manner, which decreased the mobilization of FAs from LDs degradation and hindered mitochondrial fatty acid oxidation. Mechanistically, the small ras family GTPase RAN was transcriptionally activated by CRSP8, leading to the reinforcement of RAN/CRM1-mediated nuclear export. CRSP8-induced enhanced formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer orchestrated cytoplasmic translocation of PPARα, attenuated nPPARα-mediated lipophagy and fatty acid catabolism, subsequently exacerbated HCC progression. In CRSP8-enriched HCC, lipid synthesis inhibitor Orlistat effectively reshaped the immunosuppressive tumor microenvironment (TME) and improved the efficacy of anti-PD-L1 therapy in vivo.</p><p><strong>Conclusion: </strong>Our study establishes that CRSP8-driven fatty acid metabolism reprogramming facilitates HCC progression via the RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer and impaired lipophagy-derived catabolism. Targeting the energy supply sourced from lipids could represent a promising therapeutic strategy for treating CRSP8-sufficient HCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"93"},"PeriodicalIF":11.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607073","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 interacts with nuclear PKM2 and directs histone H3 phosphorylation to promote triple-negative breast cancer metastasis.","authors":"Qixiang Li, Hongfei Ci, Pengpeng Zhao, Dongjun Yang, Yi Zou, Panhai Chen, Dongliang Wu, Wenbing Shangguan, Wenyang Li, Xingjun Meng, Mengying Xing, Yuzhong Chen, Ming Zhang, Bing Chen, Lingdong Kong, Ke Zen, David C S Huang, Zhi-Wei Jiang, Quan Zhao","doi":"10.1186/s13046-025-03343-5","DOIUrl":"10.1186/s13046-025-03343-5","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence has revealed that PKM2 has oncogenic functions independent of its canonical pyruvate kinase activity, serving as a protein kinase that regulates gene expression. However, the mechanism by which PKM2, as a histone kinase, regulates the transcription of genes involved in triple-negative breast cancer (TNBC) metastasis remains poorly understood.</p><p><strong>Methods: </strong>We integrated cellular analysis, including cell viability, proliferation, colony formation, and migration assays; biochemical assays, including protein interaction studies and ChIP; clinical sample analysis; RNA-Seq and CUT&Tag data; and xenograft or mammary-specific gene knockout mouse models, to investigate the epigenetic modulation of TNBC metastasis via NONO-dependent interactions with nuclear PKM2.</p><p><strong>Results: </strong>We report that the transcription factor NONO directly interacts with nuclear PKM2 and directs PKM2-mediated phosphorylation of histone H3 at threonine 11 (H3T11ph) to promote TNBC metastasis. We show that H3T11ph cooperates with TIP60-mediated acetylation of histone H3 at lysine 27 (H3K27ac) to activate SERPINE1 expression and to increase the proliferative, migratory, and invasive abilities of TNBC cells in a NONO-dependent manner. Conditional mammary loss of NONO or PKM2 markedly suppressed SERPINE1 expression and attenuated the malignant progression of spontaneous mammary tumors in mice. Importantly, elevated expression of NONO or PKM2 in TNBC patients is positively correlated with SERPINE1 expression, enhanced invasiveness, and poor clinical outcomes.</p><p><strong>Conclusion: </strong>These findings revealed that the NONO-dependent interaction with nuclear PKM2 is key for the epigenetic modulation of TNBC metastasis, suggesting a novel intervention strategy for treating TNBC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"90"},"PeriodicalIF":11.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587869","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":"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}