Aurora Cordaro, Maria Magdalena Barreca, Chiara Zichittella, Marco Loria, Denise Anello, Goffredo Arena, Nicolina Sciaraffa, Claudia Coronnello, Giuseppe Pizzolanti, Riccardo Alessandro, Alice Conigliaro
{"title":"Regulatory role of lncH19 in RAC1 alternative splicing: implication for RAC1B expression in colorectal cancer.","authors":"Aurora Cordaro, Maria Magdalena Barreca, Chiara Zichittella, Marco Loria, Denise Anello, Goffredo Arena, Nicolina Sciaraffa, Claudia Coronnello, Giuseppe Pizzolanti, Riccardo Alessandro, Alice Conigliaro","doi":"10.1186/s13046-024-03139-z","DOIUrl":"10.1186/s13046-024-03139-z","url":null,"abstract":"<p><p>Aberrant alternative splicing events play a critical role in cancer biology, contributing to tumor invasion, metastasis, epithelial-mesenchymal transition, and drug resistance. Recent studies have shown that alternative splicing is a key feature for transcriptomic variations in colorectal cancer, which ranks third among malignant tumors worldwide in both incidence and mortality. Long non-coding RNAs can modulate this process by acting as trans-regulatory agents, recruiting splicing factors, or driving them to specific targeted genes. LncH19 is a lncRNA dis-regulated in several tumor types and, in colorectal cancer, it plays a critical role in tumor onset, progression, and metastasis. In this paper, we found, that in colorectal cancer cells, the long non-coding RNA H19 can bind immature RNAs and splicing factors as hnRNPM and RBFOX2. Through bioinformatic analysis, we identified 57 transcripts associated with lncH19 and containing binding sites for both splicing factors, hnRNPM, and RBFOX2. Among these transcripts, we identified the mRNA of the GTPase-RAC1, whose alternatively spliced isoform, RAC1B, has been ascribed several roles in the malignant transformation. We confirmed, in vitro, the binding of the splicing factors to both the transcripts RAC1 and lncH19. Loss and gain of expression experiments in two colorectal cancer cell lines (SW620 and HCT116) demonstrated that lncH19 is required for RAC1B expression and, through RAC1B, it induces c-Myc and Cyclin-D increase. In vivo, investigation from biopsies of colorectal cancer patients showed higher levels of all the explored genes (lncH19, RAC1B, c-Myc and Cyclin-D) concerning the healthy counterpart, thus supporting our in vitro model. In addition, we identified a positive correlation between lncH19 and RAC1B in colorectal cancer patients. Finally, we demonstrated that lncH19, as a shuttle, drives the splicing factors RBFOX2 and hnRNPM to RAC1 allowing exon retention and RAC1B expression. The data shown in this paper represent the first evidence of a new mechanism of action by which lncH19 carries out its functions as an oncogene by prompting colorectal cancer through the modulation of alternative splicing.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"217"},"PeriodicalIF":11.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141890689","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}
Xiaozhu Tang, Mengjie Guo, Yuanjiao Zhang, Junxian Lv, Chunyan Gu, Ye Yang
{"title":"Examining the evidence for mutual modulation between m6A modification and circular RNAs: current knowledge and future prospects.","authors":"Xiaozhu Tang, Mengjie Guo, Yuanjiao Zhang, Junxian Lv, Chunyan Gu, Ye Yang","doi":"10.1186/s13046-024-03136-2","DOIUrl":"10.1186/s13046-024-03136-2","url":null,"abstract":"<p><p>The resistance of cancer cells to treatment significantly impedes the success of therapy, leading to the recurrence of various types of cancers. Understanding the specific mechanisms of therapy resistance may offer novel approaches for alleviating drug resistance in cancer. Recent research has shown a reciprocal relationship between circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification, and their interaction can affect the resistance and sensitivity of cancer therapy. This review aims to summarize the latest developments in the m6A modification of circRNAs and their importance in regulating therapy resistance in cancer. Furthermore, we explore their mutual interaction and exact mechanisms and provide insights into potential future approaches for reversing cancer resistance.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"216"},"PeriodicalIF":11.4,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879677","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}
Flaminia Campo, Oreste Iocca, Francesca Paolini, Valentina Manciocco, Silvia Moretto, Armando De Virgilio, Claudio Moretti, Antonello Vidiri, Aldo Venuti, Paolo Bossi, Giovanni Blandino, Raul Pellini
{"title":"The landscape of circulating tumor HPV DNA and TTMV-HPVDNA for surveillance of HPV-oropharyngeal carcinoma: systematic review and meta-analysis.","authors":"Flaminia Campo, Oreste Iocca, Francesca Paolini, Valentina Manciocco, Silvia Moretto, Armando De Virgilio, Claudio Moretti, Antonello Vidiri, Aldo Venuti, Paolo Bossi, Giovanni Blandino, Raul Pellini","doi":"10.1186/s13046-024-03137-1","DOIUrl":"10.1186/s13046-024-03137-1","url":null,"abstract":"<p><strong>Background: </strong>Human papilloma virus (HPV) related cancers of the oropharynx are rapidly increasing in incidence and may soon represent the majority of all head and neck cancers. Improved monitoring and surveillance methods are thus an urgent need in public health.</p><p><strong>Main text: </strong>The goal is to highlight the current potential and limitations of liquid biopsy through a meta analytic study on ctHPVDNA and TTMV-HPVDNA. It was performed a Literature search on articles published until December 2023 using three different databases: MEDLINE, Embase, and Cochrane Library. Studies that evaluated post-treatment ctHPVDNA and TTMV-HPVDNA in patients with HPV + OPSCC, studies reporting complete data on the diagnostic accuracy in recurrence, or in which the number of true positives, false positives, true negatives, and false negatives was extractable, and methods of detection of viral DNA clearly defined. The meta-analysis was conducted following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) reporting guidelines. The aim of this meta-analysis was to evaluate the sensitivity, specificity, and accuracy of ctHPVDNA and TTMV by ddPCR to define its efficacy in clinical setting for the follow up of HPV-OPSCC.</p><p><strong>Conclusion: </strong>The 12 studies included in the meta-analysis provided a total of 1311 patients for the analysis (398 valuated with ctHPVDNA and 913 with TTMV-HPVDNA). Pooled sensitivity and specificity were 86% (95% CI: 78%-91%) and 96% (95% CI: 91%-99%), respectively; negative and positive likelihood ratios were 0.072 (95% CI: 0.057-0.093) and 24.7 (95% CI: 6.5-93.2), respectively; pooled DOR was 371.66 (95% CI: 179.1-918). The area under the curve (AUC) was 0.81 (95% CI, 0.67-0.91). Liquid biopsy for the identification of cell free DNA might identify earlier recurrence in HPV + OPSCC patients. At the present time, liquid biopsy protocol needs to be standardized and liquid biopsy cannot yet be used in clinical setting. In the future, a multidimensional integrated approach which links multiple clinical, radiological, and laboratory data will contribute to obtain the best follow-up strategies for the follow-up of HPV-OPSCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"215"},"PeriodicalIF":11.4,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879678","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}
Alessandro Giammona, Chiara De Vellis, Enrica Crivaro, Luisa Maresca, Roberta Amoriello, Federica Ricci, Giulia Anichini, Silvia Pietrobono, David R Pease, Martin E Fernandez-Zapico, Clara Ballerini, Barbara Stecca
{"title":"Tumor-derived GLI1 promotes remodeling of the immune tumor microenvironment in melanoma.","authors":"Alessandro Giammona, Chiara De Vellis, Enrica Crivaro, Luisa Maresca, Roberta Amoriello, Federica Ricci, Giulia Anichini, Silvia Pietrobono, David R Pease, Martin E Fernandez-Zapico, Clara Ballerini, Barbara Stecca","doi":"10.1186/s13046-024-03138-0","DOIUrl":"10.1186/s13046-024-03138-0","url":null,"abstract":"<p><strong>Background: </strong>Melanoma progression is based on a close interaction between cancer cells and immune cells in the tumor microenvironment (TME). Thus, a better understanding of the mechanisms controlling TME dynamics and composition will help improve the management of this dismal disease. Work from our and other groups has reported the requirement of an active Hedgehog-GLI (HH-GLI) signaling for melanoma growth and stemness. However, the role of the downstream GLI1 transcription factor in melanoma TME remains largely unexplored.</p><p><strong>Methods: </strong>The immune-modulatory activity of GLI1 was evaluated in a syngeneic B16F10 melanoma mouse model assessing immune populations by flow cytometry. Murine polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were differentiated from bone marrow cells and their immunosuppressive ability was assessed by inhibition of T cells. Conditioned media (CM) from GLI1-overexpressing mouse melanoma cells was used to culture PMN-MDSCs, and the effects of CM were evaluated by Transwell invasion assay and T cell inhibition. Cytokine array analysis, qPCR and chromatin immunoprecipitation were performed to explore the regulation of CX3CL1 expression by GLI1. Human monocyte-derived dendritic cells (moDCs) were cultured in CM from GLI1-silenced patient-derived melanoma cells to assess their activation and recruitment. Blocking antibodies anti-CX3CL1, anti-CCL7 and anti-CXCL8 were used for in vitro functional assays.</p><p><strong>Results: </strong>Melanoma cell-intrinsic activation of GLI1 promotes changes in the infiltration of immune cells, leading to accumulation of immunosuppressive PMN-MDSCs and regulatory T cells, and to decreased infiltration of dendric cells (DCs), CD8 + and CD4 + T cells in the TME. In addition, we show that ectopic expression of GLI1 in melanoma cells enables PMN-MDSC expansion and recruitment, and increases their ability to inhibit T cells. The chemokine CX3CL1, a direct transcriptional target of GLI1, contributes to PMN-MDSC expansion and recruitment. Finally, silencing of GLI1 in patient-derived melanoma cells promotes the activation of human monocyte-derived dendritic cells (moDCs), increasing cytoskeleton remodeling and invasion ability. This phenotype is partially prevented by blocking the chemokine CCL7, but not CXCL8.</p><p><strong>Conclusion: </strong>Our findings highlight the relevance of tumor-derived GLI1 in promoting an immune-suppressive TME, which allows melanoma cells to evade the immune system, and pave the way for the design of new combination treatments targeting GLI1.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"214"},"PeriodicalIF":11.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141876557","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}
Tian Yao Liu, Jin Shan Yan, Xin Li, Lu Xu, Jun Li Hao, Su Ya Zhao, Qi Lin Hu, Fang Jian Na, He Ming Li, Yue Zhao, Ming Fang Zhao
{"title":"FGL1: a novel biomarker and target for non-small cell lung cancer, promoting tumor progression and metastasis through KDM4A/STAT3 transcription mechanism.","authors":"Tian Yao Liu, Jin Shan Yan, Xin Li, Lu Xu, Jun Li Hao, Su Ya Zhao, Qi Lin Hu, Fang Jian Na, He Ming Li, Yue Zhao, Ming Fang Zhao","doi":"10.1186/s13046-024-03140-6","DOIUrl":"10.1186/s13046-024-03140-6","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is characterized by a high incidence rate and poor prognosis worldwide. A deeper insight into the pathogenesis of NSCLC and identification of novel therapeutic targets are essential to improve the prognosis of NSCLC. In this study, we revealed that fibrinogen-like protein 1 (FGL1) promotes proliferation, migration, and invasion of NSCLC cells. Mechanistically, we found that Stat3 acts as a transcription factor and can be recruited to the FGL1 promoter, enhancing FGL1 promoter activity. Lysine-specific demethylase 4A (KDM4A) interacts with Stat3 and facilitates the removal of methyl groups from H3K9me3, thereby enhancing Stat3-mediated transcription of FGL1. Furthermore, we observed that Stat3 and KDM4A promote NSCLC cell proliferation, migration, and invasion partly by upregulating FGL1 expression. Additionally, the expression of FGL1 was significantly higher in cancer tissues (n = 90) than in adjacent non-cancerous tissues (n = 90). Furthermore, patients with high FGL1 expression had a shorter overall survival (OS) compared to those with low FGL1 expression. We measured the expression levels of FGL1 on circulating tumor cells (CTCs) in 65 patients and found that patients with a dynamic decrease in FGL1 expression on CTCs exhibited a better therapeutic response. These findings suggest that the dynamic changes in FGL1 expression can serve as a potential biomarker for predicting treatment efficacy in NSCLC. Overall, this study revealed the significant role and regulatory mechanisms of FGL1 in the development of NSCLC, suggesting its potential as a therapeutic target for patients with NSCLC. Future studies should provide more personalized and effective treatment options for patients with NSCLC to improve clinical outcomes.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"213"},"PeriodicalIF":11.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861507","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":"Inhibiting interferon-γ induced cancer intrinsic TNFRSF14 elevation restrains the malignant progression of glioblastoma.","authors":"Yunhe Han, Cunyi Zou, Tianqi Liu, Wen Cheng, Peng Cheng, Anhua Wu","doi":"10.1186/s13046-024-03131-7","DOIUrl":"10.1186/s13046-024-03131-7","url":null,"abstract":"<p><strong>Background: </strong>Prolonged interferon-γ signaling activation induces cancer resistance to therapeutics, especially immunotherapy. However, the detailed mechanisms are not well characterized. In present study, we explored cancer intrinsic resistant mechanisms employing for evading immune checkpoint blockade (ICB) and searched for key immune checkpoints contributing to the constitution of suppressive immune microenvironment of glioblastoma (GBM).</p><p><strong>Methods: </strong>We screened key immune checkpoint (IC) associated with IFN signaling activation in GBM according to integrated transcriptomic profiling on the ICs. Expression analysis and functional assays revealed that malignant cells elevated the key IC, TNFRSF14 expression under IFN-γ stimulation, which enhanced their proliferation and in vivo tumorigenicity. Therapeutic efficiency of TNFRSF14 disruption in GBM was evaluated with in vitro and in vivo functional assays, including immunofluorescence, transwell, RT-qPCR, flow cytometry, mass cytometry, and mice preclinical GBM models. Moreover, the improvement of TNFRSF14 blockade on the efficacy of PD-L1 treatment was examined in mice intracranial xenograft bearing models.</p><p><strong>Results: </strong>TNFRSF14, a previously poorly characterized IC, was disclosed as a checkpoint with malignant intrinsic elevation closely associated with type II not type I IFN signaling activation in GBM. Anti-PD-L1 treatment induces compensatory TNFRSF14 elevation, while enhancing IFN-γ production. TNFRSF14 phosphorylates FAK at Y397 and consequently activates NF-κB, which not only strengthens the tumorigenicity of GBM cells, but also enhances TAMs recruitment through elevating CXCL1/CXCL5 secretion from GBM cells. TNFRSF14 ablation reduces the tumorigenicity of GBM cells, reshapes the immunosuppressive microenvironment, and enhances therapeutic efficacy of anti-PD-L1 in mouse orthotopic GBM model.</p><p><strong>Conclusion: </strong>Our findings highlight a malignant TNFRSF14/FAK axis as a potential target to blunt cancer-intrinsic resistance to ICB treatment, which may help improve the therapeutic efficiency of immunotherapy in malignancies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"212"},"PeriodicalIF":11.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861508","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}
Marta Lopez-Cerda, Laura Lorenzo-Sanz, Victoria da Silva-Diz, Sandra Llop, Rosa M Penin, Josep Oriol Bermejo, Richard de Goeij-de Haas, Sander R Piersma, Thang V Pham, Connie R Jimenez, Juan Martin-Liberal, Purificación Muñoz
{"title":"IGF1R signaling induces epithelial-mesenchymal plasticity via ITGAV in cutaneous carcinoma.","authors":"Marta Lopez-Cerda, Laura Lorenzo-Sanz, Victoria da Silva-Diz, Sandra Llop, Rosa M Penin, Josep Oriol Bermejo, Richard de Goeij-de Haas, Sander R Piersma, Thang V Pham, Connie R Jimenez, Juan Martin-Liberal, Purificación Muñoz","doi":"10.1186/s13046-024-03119-3","DOIUrl":"10.1186/s13046-024-03119-3","url":null,"abstract":"<p><strong>Background: </strong>Early cutaneous squamous cell carcinomas (cSCCs) generally show epithelial differentiation features and good prognosis, whereas advanced cSCCs present mesenchymal traits associated with tumor relapse, metastasis, and poor survival. Currently, the mechanisms involved in cSCC progression are unclear, and the established markers are suboptimal for accurately predicting the clinical course of the disease.</p><p><strong>Methods: </strong>Using a mouse model of cSCC progression, expression microarray analysis, immunofluorescence and flow cytometry assays, we have identified a prognostic biomarker of tumor relapse, which has been evaluated in a cohort of cSCC patient samples. Phosphoproteomic analysis have revealed signaling pathways induced in epithelial plastic cancer cells that promote epithelial-mesenchymal plasticity (EMP) and tumor progression. These pathways have been validated by genetic and pharmacological inhibition assays.</p><p><strong>Results: </strong>We show that the emergence of epithelial cancer cells expressing integrin αV (ITGAV) promotes cSCC progression to a mesenchymal state. Consistently, ITGAV expression allows the identification of patients at risk of cSCC relapse above the currently employed clinical histopathological parameters. We also demonstrate that activation of insulin-like growth factor-1 receptor (IGF1R) pathway in epithelial cancer cells is necessary to induce EMP and mesenchymal state acquisition in response to tumor microenvironment-derived factors, while promoting ITGAV expression. Likewise, ITGAV knockdown in epithelial plastic cancer cells also blocks EMP acquisition, generating epithelial tumors.</p><p><strong>Conclusions: </strong>Our results demonstrate that ITGAV is a prognostic biomarker of relapse in cSCCs that would allow improved patient stratification. ITGAV also collaborates with IGF1R to induce EMP in epithelial cancer cells and promotes cSCC progression, revealing a potential therapeutic strategy to block the generation of advanced mesenchymal cSCCs.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"211"},"PeriodicalIF":11.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793952","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}
Ying Chen, Zhiyong Zhang, Fan Pan, Pengfei Li, Weiping Yao, Yuxi Chen, Lei Xiong, Tingting Wang, Yan Li, Guichun Huang
{"title":"Pericytes recruited by CCL28 promote vascular normalization after anti-angiogenesis therapy through RA/RXRA/ANGPT1 pathway in lung adenocarcinoma.","authors":"Ying Chen, Zhiyong Zhang, Fan Pan, Pengfei Li, Weiping Yao, Yuxi Chen, Lei Xiong, Tingting Wang, Yan Li, Guichun Huang","doi":"10.1186/s13046-024-03135-3","DOIUrl":"10.1186/s13046-024-03135-3","url":null,"abstract":"<p><strong>Background: </strong>It has been proposed that anti-angiogenesis therapy could induce tumor \"vascular normalization\" and further enhance the efficacy of chemotherapy, radiotherapy, target therapy, and immunotherapy for nearly twenty years. However, the detailed molecular mechanism of this phenomenon is still obscure.</p><p><strong>Method: </strong>Overexpression and knockout of CCL28 in human lung adenocarcinoma cell line A549 and murine lung adenocarcinoma cell line LLC, respectively, were utilized to establish mouse models. Single-cell sequencing was performed to analyze the proportion of different cell clusters and metabolic changes in the tumor microenvironment (TME). Immunofluorescence and multiplex immunohistochemistry were conducted in murine tumor tissues and clinical biopsy samples to assess the percentage of pericytes coverage. Primary pericytes were isolated from lung adenocarcinoma tumor tissues using magnetic-activated cell sorting (MACS). These pericytes were then treated with recombinant human CCL28 protein, followed by transwell migration assays and RNA sequencing analysis. Changes in the secretome and metabolome were examined, and verification of retinoic acid metabolism alterations in pericytes was conducted using quantitative real-time PCR, western blotting, and LC-MS technology. Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) was employed to validate the transcriptional regulatory ability and affinity of RXRα to specific sites at the ANGPT1 promoter.</p><p><strong>Results: </strong>Our study showed that after undergoing anti-angiogenesis treatment, the tumor exhibited a state of ischemia and hypoxia, leading to an upregulation in the expression of CCL28 in hypoxic lung adenocarcinoma cells by the hypoxia-sensitive transcription factor CEBPB. Increased CCL28 could promote tumor vascular normalization through recruiting and metabolic reprogramming pericytes in the tumor microenvironment. Mechanistically, CCL28 modified the retinoic acid (RA) metabolism and increased ANGPT1 expression via RXRα in pericytes, thereby enhancing the stability of endothelial cells.</p><p><strong>Conclusion: </strong>We reported the details of the molecular mechanisms of \"vascular normalization\" after anti-angiogenesis therapy for the first time. Our work might provide a prospective molecular marker for guiding the clinical arrangement of combination therapy between anti-angiogenesis treatment and other therapies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"210"},"PeriodicalIF":11.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793953","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}
Adriana Rosa Gambardella, Caterina Antonucci, Cristiana Zanetti, Francesco Noto, Sara Andreone, Davide Vacca, Valentina Pellerito, Chiara Sicignano, Giuseppe Parrottino, Valentina Tirelli, Antonella Tinari, Mario Falchi, Adele De Ninno, Luca Businaro, Stefania Loffredo, Gilda Varricchi, Claudio Tripodo, Claudia Afferni, Isabella Parolini, Fabrizio Mattei, Giovanna Schiavoni
{"title":"IL-33 stimulates the anticancer activities of eosinophils through extracellular vesicle-driven reprogramming of tumor cells.","authors":"Adriana Rosa Gambardella, Caterina Antonucci, Cristiana Zanetti, Francesco Noto, Sara Andreone, Davide Vacca, Valentina Pellerito, Chiara Sicignano, Giuseppe Parrottino, Valentina Tirelli, Antonella Tinari, Mario Falchi, Adele De Ninno, Luca Businaro, Stefania Loffredo, Gilda Varricchi, Claudio Tripodo, Claudia Afferni, Isabella Parolini, Fabrizio Mattei, Giovanna Schiavoni","doi":"10.1186/s13046-024-03129-1","DOIUrl":"10.1186/s13046-024-03129-1","url":null,"abstract":"<p><p>Immune cell-derived extracellular vesicles (EV) affect tumor progression and hold promise for therapeutic applications. Eosinophils are major effectors in Th2-related pathologies recently implied in cancer. Here, we evaluated the anti-tumor activities of eosinophil-derived EV following activation with the alarmin IL-33. We demonstrate that IL-33-activated mouse and human eosinophils produce higher quantities of EV with respect to eosinophils stimulated with IL-5. Following incorporation of EV from IL-33-activated eosinophils (Eo33-EV), but not EV from IL-5-treated eosinophils (Eo5-EV), mouse and human tumor cells increased the expression of cyclin-dependent kinase inhibitor (CDKI)-related genes resulting in cell cycle arrest in G0/G1, reduced proliferation and inhibited tumor spheroid formation. Moreover, tumor cells incorporating Eo33-EV acquired an epithelial-like phenotype characterized by E-Cadherin up-regulation, N-Cadherin downregulation, reduced cell elongation and migratory extent in vitro, and impaired capacity to metastasize to lungs when injected in syngeneic mice. RNA sequencing revealed distinct mRNA signatures in Eo33-EV and Eo5-EV with increased presence of tumor suppressor genes and enrichment in pathways related to epithelial phenotypes and negative regulation of cellular processes in Eo33-EV compared to Eo5-EV. Our studies underscore novel IL-33-stimulated anticancer activities of eosinophils through EV-mediated reprogramming of tumor cells opening perspectives on the use of eosinophil-derived EV in cancer therapy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"209"},"PeriodicalIF":11.4,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767961","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}
Yixun Zhang, Yumeng Yang, Xuan Qi, Peng Cui, Yi Kang, Haiyi Liu, Zhigang Wei, Haibo Wang
{"title":"SLC14A1 and TGF-β signaling: a feedback loop driving EMT and colorectal cancer metachronous liver metastasis.","authors":"Yixun Zhang, Yumeng Yang, Xuan Qi, Peng Cui, Yi Kang, Haiyi Liu, Zhigang Wei, Haibo Wang","doi":"10.1186/s13046-024-03114-8","DOIUrl":"10.1186/s13046-024-03114-8","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) metachronous liver metastasis is a significant clinical challenge, largely attributable to the late detection and the intricate molecular mechanisms that remain poorly understood. This study aims to elucidate the role of Solute Carrier Family 14 Member 1 (SLC14A1) in the pathogenesis and progression of CRC metachronous liver metastasis.</p><p><strong>Methods: </strong>We conducted a comprehensive analysis of CRC patient data from The Cancer Genome Atlas and GSE40967 databases, focusing on the differential expression of genes associated with non-metachronous liver metastasis and metachronous liver metastasis. Functional assays, both in vitro and in vivo, were performed to assess the biological impact of SLC14A1 modulation in CRC cells. Gene set enrichment analysis, molecular assays and immunohistochemical analyses on clinical specimens were employed to unravel the underlying mechanisms through which SLC14A1 exerts its effects.</p><p><strong>Results: </strong>SLC14A1 was identified as a differentially expressed gene, with its overexpression significantly correlating with poor relapse-free and overall survival. Mechanistically, elevated SLC14A1 levels enhanced CRC cell invasiveness and migratory abilities, corroborated by upregulated TGF-β/Smad signaling and Epithelial-Mesenchymal Transition. SLC14A1 interacted with TβRII and stabilized TβRII protein, impeding its Smurf1-mediated K48-linked ubiquitination and degradation, amplifying TGF-β/Smad signaling. Furthermore, TGF-β1 reciprocally elevated SLC14A1 mRNA expression, with Snail identified as a transcriptional regulator, binding downstream of SLC14A1's transcription start site, establishing a positive feedback loop. Clinically, SLC14A1, phosphorylated Smad2, and Snail were markedly upregulated in CRC patients with metachronous liver metastasis, underscoring their potential as prognostic markers.</p><p><strong>Conclusions: </strong>Our findings unveil SLC14A1 as a critical regulator in CRC metachronous liver metastasis, providing novel insights into the molecular crosstalk between SLC14A1 and TGF-β/Smad signaling. These discoveries not only enhance our understanding of CRC metachronous liver metastasis pathogenesis, but also highlight SLC14A1 as a promising target for therapeutic intervention and predictive marker.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"43 1","pages":"208"},"PeriodicalIF":11.4,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767962","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}