Experimental Hematology & Oncology最新文献

{"title":"Unravelling neutropenic enterocolitis: insights from gut microbiota, and intestinal barrier analyses.","authors":"Natacha Kapandji, Maud Salmona, Anaïs Lemoine, Guillaume Ulmann, Julien Calderaro, Brigitte Roche, Nathalie Kapel, Lucie Biard, Etienne Lengline, Jérôme Le Goff, Christophe Rodriguez, Muriel Thomas, Lara Zafrani","doi":"10.1186/s40164-025-00661-4","DOIUrl":"https://doi.org/10.1186/s40164-025-00661-4","url":null,"abstract":"<p><strong>Background: </strong>Neutropenic enterocolitis (NE) is a severe digestive complication of chemotherapy, primarily affecting patients with acute myeloid leukemia (AML). We hypothesized that NE is linked to intestinal barrier dysfunction and gut dysbiosis.</p><p><strong>Methods: </strong>Sixty-five AML patients undergoing induction chemotherapy were included in this prospective monocentric cohort. Among them, 26 patients (40%) were diagnosed with NE. Stool samples were subjected to bacterial load quantification (all bacteria quantitative PCR), 16s rRNA metagenomic analysis, and short-chain-fatty-acids quantification. Additionally, fecal calprotectin and human 𝛃-defensin 2 along with plasmatic inflammatory cytokines, and citrulline levels were measured. Human transcriptomic analysis was conducted on samples obtained from anatomical specimens of colectomies of NE patients.</p><p><strong>Results: </strong>Gut microbiota underwent significant alterations after chemotherapy, transitioning from a diverse and balanced enterotype to enterotypes exhibiting a reduced α-diversity, an increased abundance of Enterococcus faecalis, and a decreased abundance of butyrate-producing genera, which correlated with a decreased fecal concentration of butyrate. Simultaneously, post-chemotherapy, plasma citrulline concentrations decreased indicating enterocyte damages. Finally, human transcriptomic analysis found a significant upregulation of the JAK-STAT signaling KEGG pathway in the colons of NE patients encompassing cytokines (IL-6, OSM-OSMR) that play a pivotal role in sustaining local inflammation within the digestive tract.</p><p><strong>Conclusions: </strong>This work reaffirms the significant influence of chemotherapy on the gut microbiota and the integrity of the enterocyte barrier. Severe NE is marked by the development of a local inflammatory response that may be induced by the reduction in butyrate levels.</p><p><strong>Trial registration: </strong>The study was registered on Clinicaltrials.gov (identifier: NCT04438278).</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"74"},"PeriodicalIF":9.4,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A correlation of ineffective erythropoiesis and dysregulated signaling pathways in myelodysplastic syndromes/neoplasms.","authors":"Junying Wu, Jinqin Liu, Jia Chen, Lin Yang, Fuhui Li, Tiejun Qin, Zefeng Xu, Jing Liu, Jiaxi Zhou, Lihong Shi, Bing Li, Zhijian Xiao","doi":"10.1186/s40164-025-00664-1","DOIUrl":"https://doi.org/10.1186/s40164-025-00664-1","url":null,"abstract":"<p><p>Over 90% of patients with myelodysplastic syndromes/neoplasms (MDS) exhibit anemia at diagnosis, primarily due to ineffective erythropoiesis. This is characterized by abnormal proliferation and differentiation of erythroid cells influenced by signaling pathways including heme synthesis, ferroptosis, senescence and apoptosis. Despite widespread anemia, the specific mechanisms and pathway alterations at different disease stages are not well understood. This study employed the NUP98-HOXD13 (NHD13) transgenic mouse model, which mimicked the erythroid changes observed in MDS patients, to explore these dynamic pathway changes during disease progression. Based on the severity of anemia and changes in mean corpuscular volume (MCV), four time points were selected: 6 weeks (non-anemic), 12 weeks (mild anemia), 16 weeks (obvious anemia) and 20 weeks (severe macrocytic anemia). The findings indicated that a reduction in erythroid-committed progenitors and impaired erythroid maturation were linked to ineffective erythropoiesis. As the disease progressed, signaling pathways dynamically changed. Heme metabolism and ferroptosis pathways were significantly upregulated in the pre-disease and early disease stages, while senescence and cell cycle pathways were activated in the early stage. The prominent roles of apoptosis, pyroptosis and inflammasome signaling pathways were observed in the late stage. Notably, changes in Gpx4 and Ncoa4 expression, along with transmission electron microscopy analysis, suggested that ferroptosis played a critical role in the early stage of the disease. To our knowledge, this is the first report of the signaling pathway dynamics associated with ineffective erythropoiesis during the pathogenesis and progression of MDS, highlighting potential targets for therapeutic intervention at various stages of the disease.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"71"},"PeriodicalIF":9.4,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076514","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":"Superiority of targeted RNA sequencing for fusion detection and subtype diagnosis in Chinese sarcoma patients: a multicenter study.","authors":"Gu Jin, Dandan Zhao, Baoming Wang, Xuejiao Liu, Quanyu Yang, Zhengchuang Liu, Qiong Yang, Jianhua Zhu, Jie Zhang, Wei Li, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, Jiayong Liu","doi":"10.1186/s40164-025-00663-2","DOIUrl":"https://doi.org/10.1186/s40164-025-00663-2","url":null,"abstract":"<p><p>Sarcomas are rare, heterogeneous mesenchymal malignancies with notably high misdiagnosis rates. Despite sarcoma patients in China representing about one-quarter of the global disease burden, large-scale NGS-based diagnostic studies remain scarce, with limited sample sizes failing to capture the extensive subtype complexity of sarcomas. To address diagnostic gaps, we conducted the largest multicenter study in China involving 788 patients with soft tissue or bone sarcomas. All samples underwent targeted RNA sequencing (Fusioncapture) alongside standard histopathology, immunohistochemistry, and DNA-based next-generation sequencing (NGS). Compared with DNA-NGS, RNA-based profiling clarified ambiguous fusion calls and uncovered numerous additional and clinically relevant events, including 281 fusions not captured by the DNA panel. Notably, 114 recurrent alterations were strongly subtype-associated, and 20 newly identified receptor tyrosine kinase fusions had therapeutic significance, expanding targetable cases from 3.3% to 6.5%. Furthermore, integrated RNA data led to subtype reclassification in 11.9% of patients, including 22% of those initially diagnosed as \"not otherwise specified\". These findings confirm the utility of targeted RNA sequencing for detecting transcriptionally active fusions, refining pathological classifications, and identifying actionable variants in Chinese sarcoma patients. Despite retrospective design and limited orthogonal validation of some fusions, our results strongly support incorporating RNA-based assays into routine clinical workflows. Ultimately, this integrated approach can improve diagnostic precision, guide personalized treatment strategies, and enhance outcomes for sarcoma patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"70"},"PeriodicalIF":9.4,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076717","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":"Epstein-Barr virus infection following allogeneic hematopoietic stem cell transplantation in the era of letermovir for cytomegalovirus prophylaxis.","authors":"Jingtao Huang, Jing Zhou, Shixuan Zhang, Ruoxuan Zhang, Zengkai Pan, Luxiang Wang, Chuanhe Jiang, Jiayu Huang, Zilu Zhang, Yanmin Zhao, Yang Cao, Xiaoxia Hu","doi":"10.1186/s40164-025-00665-0","DOIUrl":"https://doi.org/10.1186/s40164-025-00665-0","url":null,"abstract":"<p><p>Letermovir is an antiviral agent that significantly decreases the frequency of cytomegalovirus (CMV) infections following allogeneic hematopoietic stem cell transplantation (allo-HCT); however, its impact on Epstein-Barr virus (EBV) infection remains unclear. This multicenter, retrospective study involved 565 patients aged ≥ 18 years, who underwent allo-HCT between January 2021 and December 2023, with 284 receiving letermovir prophylaxis (letermovir group) and 281 not (control group). Cumulative incidences of clinically significant CMV infection (cs-CMVi), EBV DNAemia, EBV-disease and post-transplant lymphoproliferative disorder (PTLD) were compared between the groups. The 1-year cumulative incidence of EBV DNAemia did not differ significantly between the letermovir and control groups (58.1% vs. 52.7%, P = 0.3). However, letermovir prophylaxis was associated with a significantly higher incidence of PTLD within the first year post-HCT (7.39% vs. 1.80%, P = 0.00059). Multivariate analysis identified letermovir prophylaxis as an independent risk factor for PTLD (HR [95% CI]: 4.619 [1.458-10.278], P = 0.007). Letermovir altered the early reconstitution trajectory after allo-HCT, particularly in CD8⁺ T cells. Our findings emphasized that although letermovir prophylaxis did not increase the risk of EBV DNAemia in allo-HCT recipients, it was associated with a higher incidence of PTLD. Further studies focusing on immune reconstitutiom dynamics are warranted to elucidate the underlying pathophysiology of EBV-PTLD under letermovir pressure.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"72"},"PeriodicalIF":9.4,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076632","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":"Impact of diagnosis to treatment interval on outcomes in patients with newly diagnosed marginal zone lymphoma - a US multisite study.","authors":"Narendranath Epperla, Geoffrey Shouse, Natalie S Grover, Pallawi Torka, Kaitlin Annunzio, Marcus Watkins, Andrea Anampa-Guzmán, Beth Christian, Colin Thomas, Stefan K Barta, Praveen Ramakrishnan Geethakumari, Reem Karmali, Nancy L Bartlett, Adam J Olszewski","doi":"10.1186/s40164-025-00666-z","DOIUrl":"https://doi.org/10.1186/s40164-025-00666-z","url":null,"abstract":"<p><p>Diagnosis-to-treatment interval (DTI) is an important prognostic factor in patients with newly diagnosed aggressive lymphomas, however the impact of DTI on outcomes in marginal zone lymphoma (MZL) is unknown. In this multicenter retrospective cohort study, we included adult patients with MZL who received first-line immunochemotherapy within 120 days of diagnosis at 10 US medical centers. Patients who received treatment within 60 days from their diagnosis were classified into the short DTI group and those who received treatment beyond 60 days into long DTI group. The primary objective was progression-free survival (PFS), while secondary objectives included overall survival (OS) and cumulative incidence of histologic transformation (HT) between the two groups. Of the 870 patients with newly diagnosed MZL, 177 patients met the inclusion criteria and were included in this analysis. Among these 144 (81%) were in the short DTI group and 33 (19%) in the long DTI group. In the univariable analysis, presence of B symptoms was associated with short DTI and remained significantly associated with short DTI in the multivariable analysis (OR = 11.91, p = 0.017). Short DTI was not associated with a statistically different PFS or OS compared to long DTI in the univariable or in multivariable analysis. The cumulative incidence of HT was not significantly different between the two groups. This is the first study to-date to report on the association of DTI on outcomes in MZL patients. This lack of prognostic utility of DTI in newly diagnosed MZL, in contrast to aggressive B-cell lymphomas, may be intrinsically linked to the underlying disease biology.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"73"},"PeriodicalIF":9.4,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076635","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":"Molecular mechanisms of viral oncogenesis in haematological malignancies: perspectives from metabolic reprogramming, epigenetic regulation and immune microenvironment remodeling.","authors":"Qing Xiao, Yi Liu, Xuejiao Shu, Ya Li, Xiaomei Zhang, Chaoyu Wang, Sanxiu He, Jun Li, Tingting Li, Tingting Liu, Yao Liu","doi":"10.1186/s40164-025-00655-2","DOIUrl":"https://doi.org/10.1186/s40164-025-00655-2","url":null,"abstract":"<p><p>Haematological malignancies are one of the most common tumors, with a rising incidence noted over recent decades. Viral infections play significant roles in the pathogenesis of these malignancies globally. This review delves into the contributions of various known viruses-specifically Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), human T-cell leukemia virus type 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), human cytomegalovirus (HCMV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human papillomavirus (HPV)-in the development of haematological malignancies. These viruses are shown to drive tumorigenesis through mechanisms, such as metabolic reprogramming, epigenetic modifications, and remodeling of the immune microenvironment. By directly disrupting fundamental cellular functions and altering metabolic and epigenetic pathways, these viruses foster an immune milieu that supports both viral persistence and tumor growth. A thorough understanding of these viral oncogenic processes is crucial not only for etiological discovery but also for developing targeted interventions. This review emphasizes the need for continued research into the specific ways these viruses manipulate the host cell's metabolic and epigenetic environments, aiming to provide insights that could guide future advancements in treatment modalities.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"69"},"PeriodicalIF":9.4,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999317","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":"Cardiotoxicity of small-molecule kinase inhibitors in cancer therapy.","authors":"Shuangli Zhu, Kai Fu, Sijia Li, Chuan Yang, Can Pan, Xueping Wang, Fang Wang, Xiyong Yu, Kenneth Kin Wah To, Liwu Fu","doi":"10.1186/s40164-025-00660-5","DOIUrl":"https://doi.org/10.1186/s40164-025-00660-5","url":null,"abstract":"<p><p>Cancer is one of the leading causes of death worldwide. Recent advances in precision oncology have enabled many specific cancer patient populations to respond well and achieve longer survival with small-molecule kinase inhibitors, which have become a new therapeutic strategy for tumors. Since 2001, the Food and Drug Administration has approved 108 and 63 new anticancer drugs for treating solid tumors and hematological malignancies, respectively, 89 of which belong to the large group of small-molecule kinase inhibitors (SMKIs). Compared to conventional chemotherapeutic agents such as cyclophosphamide, doxorubicin, and 5-FU, SMKIs offer better efficacy with fewer toxic side effects. Nevertheless, with the development of more novel SMKIs and their wider clinical application to a larger population of cancer patients, variable degrees of cardiotoxic adverse events have emerged for some SMKIs during cancer therapy. This review comprehensively summarizes the most updated progress in the cardiotoxicity of SMKIs in cancer therapy and discusses the new findings and mechanisms, which will provide emerging strategies for the prevention of cardiotoxicity caused by small molecule targeted drugs and the design of the next generation of low cardiotoxicity targeted drugs.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"68"},"PeriodicalIF":9.4,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005193","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":"Transcriptomic profiling of circulating tumor cells from metastatic breast cancer patients reveals new hints in their biological features and phenotypic heterogeneity.","authors":"Tania Rossi, Sara Bandini, Michele Zanoni, Michela Cortesi, Michela Palleschi, Erika Bandini, Andrea Rocca, Giulia Gallerani, Ivan Vannini, Meropi Plousiou, Lorenzo Gerratana, Antonino Musolino, Giovanni Tallini, Giovanni Martinelli, Ugo De Giorgi, Paola Ulivi","doi":"10.1186/s40164-025-00659-y","DOIUrl":"https://doi.org/10.1186/s40164-025-00659-y","url":null,"abstract":"<p><p>The study of circulating tumor cells (CTCs) provides critical insights into the biological mechanisms underlying metastasis. This study aims to demonstrate the applicability of an integrated DEPArray-based phenotypic analysis combined with transcriptomic characterization to investigate the biology of CTCs isolated from 10 patients with metastatic breast cancer (MBC). The transcriptional profiles of CTCs were consistent with both the cancer type and epithelial characteristics. Gene set enrichment analysis identified pathways associated with synapse organization and calcium channel activity. Furthermore, distinct gene expression profiles were linked to specific metastatic sites, particularly bone metastases. We also report a rare and understudied population of CTCs, characterized by the co-expression of epithelial and leukocyte markers, observed exclusively in patient-derived samples and not in blood samples from healthy volunteers spiked with SKBR-3 and MCF-7 cell lines. This suggests that these double-positive CTCs (dpCTCs) may have a specific role in the metastatic process. The transcriptomic characterization of these rare CTCs enhances our understanding of their biology and potential involvement in metastasis. As a pilot study, our findings underscore the potential of CTC-based transcriptomics as a valuable tool for advancing clinical and biological understanding of MBC, particularly regarding metastatic mechanisms and organotropism. Moreover, it provides preliminary insights into dpCTCs, a poorly characterized population that may play a pivotal role in metastasis but remains largely unexplored. These findings could pave the way for developing targeted therapies aimed at the pathways driving metastasis and for improving patient monitoring through CTC profiling.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"67"},"PeriodicalIF":9.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting immune checkpoints in hepatocellular carcinoma therapy: toward combination strategies with curative potential.","authors":"Jing Tong, Yongci Tan, Wenwen Ouyang, Haocai Chang","doi":"10.1186/s40164-025-00636-5","DOIUrl":"https://doi.org/10.1186/s40164-025-00636-5","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"65"},"PeriodicalIF":9.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964948","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":"IL-6-mediated tumorigenicity and antioxidant state in squamous cell carcinoma cells are driven by CD109 via stabilization of IL-6 receptor-alpha and activation of STAT3/NRF2 pathway.","authors":"Amani Hassan, Tenzin Kungyal, Shufeng Zhou, Meryem Blati, Kenneth Finnson, Nick Bertos, Nahid Golabi, Nader Sadeghi, Sampath Loganathan, Anie Philip","doi":"10.1186/s40164-025-00630-x","DOIUrl":"https://doi.org/10.1186/s40164-025-00630-x","url":null,"abstract":"<p><strong>Background: </strong>Squamous cell carcinoma (SCC) is a prevalent malignancy and there are limited options to block the recurrence and metastasis that often occur in SCC patients. Although IL-6, a proinflammatory cytokine, is strongly implicated in SCC pathogenesis, its mechanism of action is poorly understood. The GPI-anchored membrane protein CD109 is frequently overexpressed in SCC and is associated with malignant transformation. The current study aims to investigate whether CD109 interacts with IL-6 receptor alpha (IL6Rα) and promotes IL-6-mediated oncogenic signaling to drive SCC progression.</p><p><strong>Methods: </strong>IL6Rα interaction with CD109 was determined by coimmunoprecipitation, immunohistochemistry, immunofluorescence and FACS analysis using human SCC (oral and vulvar) cell lines and human oral SCC tumors versus control tissue. Regulation of IL-6-induced signaling and antioxidant responses by CD109 was analyzed via STAT3/NRF2/SOD1/HO1 pathway activation. Regulation of IL-6-mediated tumorigenicity by CD109 was determined using stem cell marker expression and a spheroid formation assay. Clinical validation was achieved using genomic and proteomic analysis of oral SCC tumors and of head and neck SCC patient data.</p><p><strong>Results: </strong>We show that CD109 interacts with and stabilizes IL6Rα expression and promotes IL-6/STAT3/NRF2 pathway in oral and vulvar SCC cells. Loss of CD109 attenuates this pathway leading to loss of cancer cell stemness and decreased expression of superoxide dismutase1 and heme oxygenase-1, antioxidant proteins important for cell survival after chemotherapy. Furthermore, clinical validation of these findings was achieved through multi-omic analysis of oral SCC tumors and of head and neck SCC patient data.</p><p><strong>Conclusions: </strong>This work uncovers a previously unidentified mechanism in which CD109 serves as an essential regulator of IL6Rα expression and IL-6 mediated signaling in SCC cells, promoting stemness and antioxidant state, mechanisms known to mediate therapy resistance in SCC. Our findings establish a mechanistic validation for investigating the therapeutic utility of the CD109/ IL6Rα/STAT3/NRF2 pathway in SCC.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"64"},"PeriodicalIF":9.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990778","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}