Journal of Experimental & Clinical Cancer Research最新文献

{"title":"E. Coli cytotoxic necrotizing factor-1 promotes colorectal carcinogenesis by causing oxidative stress, DNA damage and intestinal permeability alteration.","authors":"Michela Tozzi, Alessia Fiore, Sara Travaglione, Francesca Marcon, Gabriella Rainaldi, Elena Angela Pia Germinario, Ilenia Laterza, Simona Donati, Daniele Macchia, Massimo Spada, Omar Leoni, Maria Cristina Quattrini, Donatella Pietraforte, Sofia Tomasoni, Filippo Torrigiani, Ranieri Verin, Paola Matarrese, Lucrezia Gambardella, Francesca Spadaro, Maria Carollo, Agostina Pietrantoni, Francesca Carlini, Concetta Panebianco, Valerio Pazienza, Filomena Colella, Donatella Lucchetti, Alessandro Sgambato, Antonella Sistigu, Federica Moschella, Marco Guidotti, Olimpia Vincentini, Zaira Maroccia, Mauro Biffoni, Roberta De Angelis, Laura Bracci, Alessia Fabbri","doi":"10.1186/s13046-024-03271-w","DOIUrl":"10.1186/s13046-024-03271-w","url":null,"abstract":"<p><strong>Background: </strong>Bacterial toxins are emerging as promising hallmarks of colorectal cancer (CRC) pathogenesis. In particular, Cytotoxic Necrotizing Factor 1 (CNF1) from E. coli deserves special consideration due to the significantly higher prevalence of this toxin gene in CRC patients with respect to healthy subjects, and to the numerous tumor-promoting effects that have been ascribed to the toxin in vitro. Despite this evidence, a definitive causal link between CNF1 and CRC was missing. Here we investigated whether CNF1 plays an active role in CRC onset by analyzing pro-carcinogenic key effects specifically induced by the toxin in vitro and in vivo.</p><p><strong>Methods: </strong>Viability assays, confocal microscopy of γH2AX and 53BP1 molecules and cytogenetic analysis were carried out to assess CNF1-induced genotoxicity on non-neoplastic intestinal epithelial cells. Caco-2 monolayers and 3D Caco-2 spheroids were used to evaluate permeability alterations specifically induced by CNF1, either in the presence or in the absence of inflammation. In vivo, an inflammatory bowel disease (IBD) model was exploited to evaluate the carcinogenic potential of CNF1. Immunohistochemistry and immunofluorescence stainings of formalin-fixed paraffin-embedded (FFPE) colon tissue were carried out as well as fecal microbiota composition analysis by 16 S rRNA gene sequencing.</p><p><strong>Results: </strong>CNF1 induces the release of reactive oxidizing species and chromosomal instability in non-neoplastic intestinal epithelial cells. In addition, CNF1 modifies intestinal permeability by directly altering tight junctions' distribution in 2D Caco-2 monolayers, and by hindering the differentiation of 3D Caco-2 spheroids with an irregular arrangement of these junctions. In vivo, repeated intrarectal administration of CNF1 induces the formation of dysplastic aberrant crypt foci (ACF), and produces the formation of colorectal adenomas in an IBD model. These effects are accompanied by the increased neutrophilic infiltration in colonic tissue, by a mixed pro-inflammatory and anti-inflammatory cytokine milieu, and by the pro-tumoral modulation of the fecal microbiota.</p><p><strong>Conclusions: </strong>Taken together, our results support the hypothesis that the CNF1 toxin from E. coli plays an active role in colorectal carcinogenesis. Altogether, these findings not only add new knowledge to the contribution of bacterial toxins to CRC, but also pave the way to the implementation of current screening programs and preventive strategies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"29"},"PeriodicalIF":11.4,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061312","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":"Allogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHD.","authors":"Jongbok Lee, Hyeonjeong Kang, Branson Chen, Yoosu Na, Ismat Khatri, Fraser Soares, Housheng Hansen He, Arjun D Law, Tianzhong Pan, Armin Gerbitz, Xiaoyu Zhu, Mark D Minden, Li Zhang","doi":"10.1186/s13046-024-03247-w","DOIUrl":"10.1186/s13046-024-03247-w","url":null,"abstract":"<p><p>Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a second-line treatment with curative potential for leukemia patients. However, the prognosis of allo-HSCT patients with disease relapse or graft-versus-host disease (GvHD) is poor. CD4⁺ or CD8⁺ conventional T (Tconv) cells are critically involved in mediating anti-leukemic immune responses to prevent relapse and detrimental GvHD. Hence, treatment for one increases the risk of the other. Thus, therapeutic strategies that can address relapse and GvHD are considered the Holy Grail of allo-HSCT. CD3⁺CD4^-CD8^- double-negative T cells (DNTs) are unconventional mature T cells with potent anti-leukemia effects with \"off-the-shelf\" potential. A phase I clinical trial demonstrated the feasibility, safety, and potential efficacy of allogeneic DNT therapy for patients with relapsing acute myeloid leukemia (AML) post-allo-HSCT. Here, we studied the impact of DNTs on the anti-leukemic and GvHD-inducing activities of Tconv cells. DNTs synergized with Tconv cells to mediate superior anti-leukemic activity. Mechanistically, DNTs released soluble factors which activated and evoked potent anti-leukemic activities of Tconv cells. In contrast, DNTs suppressed GvHD-inducing activities of Tconv cells in a CD18-dependent manner by mediating cytotoxicity against proliferative Tconv cells. The seemingly opposite immunological activities of DNTs were dictated by the presence or absence of AML cells. Collectively, these results support the potential of DNTs as an adjuvant to allo-HSCT to address both disease relapse and GvHD.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"28"},"PeriodicalIF":11.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061308","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 identify a novel macrophage population associated with bone invasion in pituitary neuroendocrine tumors.","authors":"Xinzhi Wu, Xueshuai Han, Haibo Zhu, Mingxuan Li, Lei Gong, Sicheng Jing, Weiyan Xie, Zhaoqi Liu, Chuzhong Li, Yazhuo Zhang","doi":"10.1186/s13046-025-03296-9","DOIUrl":"10.1186/s13046-025-03296-9","url":null,"abstract":"<p><strong>Background: </strong>Bone-invasive Pituitary Neuroendocrine Tumors (BI PitNETs) epitomize an aggressive subtype of pituitary tumors characterized by bone invasion, culminating in extensive skull base bone destruction and fragmentation. This infiltration poses a significant surgical risk due to potential damage to vital nerves and arteries. However, the mechanisms underlying bone invasion caused by PitNETs remain elusive, and effective interventions for PitNET-induced bone invasion are lacking in clinical practice.</p><p><strong>Methods: </strong>In this study, we performed single-cell (n = 87,287) RNA sequencing on 10 cases of bone-invasive PitNETs and 5 cases of non-bone-invasion PitNETs (Non-BI PitNETs). We identified various cell types and determined their interactions through cell-cell communication analysis, which was further validated experimentally.</p><p><strong>Results: </strong>We identified a novel TNF-α⁺ TAM macrophage subset. BI PitNETs showed increased IL-34 secretion, impacting TNF-α⁺ TAMs via the IL34/CSF1R axis, leading to TNF-α production. TNF-α⁺ TAMs, in turn, communicate with CD14⁺ monocytes to promote their differentiation into osteoclasts and leading to bone invasion. In addition, we defined a gene signature for TNF-α⁺ TAM to guide the clinical prognosis prediction of BI PitNETs.</p><p><strong>Conclusions: </strong>Our study elucidates the tumor microenvironment changes in bone invasion and identifies the critical role of TNF-α⁺ TAMs in promoting bone invasion of PitNETs, laying a foundation for developing new molecular markers or therapeutic agents targeting BI PitNETs.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"27"},"PeriodicalIF":11.4,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048452","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":"CASC8 activates the pentose phosphate pathway to inhibit disulfidptosis in pancreatic ductal adenocarcinoma though the c-Myc-GLUT1 axis.","authors":"Hong-Fei Yao, Jieqiong Ge, Jiahao Chen, Xiaoyan Tang, Chunjing Li, Xiao Hu, Abousalam Abdoulkader Ahmed, Yunlong Pu, Guihua Zhou, Tongyi Zhang, Zhiwei Cai, Chongyi Jiang","doi":"10.1186/s13046-025-03295-w","DOIUrl":"10.1186/s13046-025-03295-w","url":null,"abstract":"<p><strong>Purpose: </strong>Glucose starvation induces the accumulation of disulfides and F-actin collapse in cells with high expression of SLC7A11, a phenomenon termed disulfidptosis. This study aimed to confirm the existence of disulfidptosis in pancreatic ductal adenocarcinoma (PDAC) and elucidate the role of Cancer Susceptibility 8 (CASC8) in this process.</p><p><strong>Methods: </strong>The existence of disulfidptosis in PDAC was assessed using flow cytometry and F-actin staining. CASC8 expression and its clinical correlations were analyzed using data from The Cancer Genome Atlas (TCGA) and further verified by chromogenic in situ hybridization assay in PDAC tissues. Cells with CASC8 knockdown and overexpression were subjected to cell viability, EdU, transwell assays, and used to establish subcutaneous and orthotopic tumor models. Disulfidptosis was detected by flow cytometry and immunofluorescence assays. RNA sequencing and metabolomics analysis were performed to determine the metabolic pathways which were significantly affected after CASC8 knockdown. We detected the glucose consumption and the NADP⁺/NADPH ratio to investigate alterations in metabolic profiles. RNA immunoprecipitation combined with fluorescence in situ hybridization assay was used to identify protein-RNA interactions. Protein stability, western blotting and quantitative real-time PCR assays were performed to reveal potential molecular mechanism.</p><p><strong>Results: </strong>Disulfidptosis was observed in PDAC and could be significantly rescued by disulfidptosis inhibitors. CASC8 expression was higher in PDAC samples compared to normal pancreatic tissue. High CASC8 expression correlated with a poor prognosis for patients with PDAC and contributed to cancer progression in vitro and in vivo. Furthermore, CASC8 was associated with disulfidptosis resistance under glucose starvation conditions in PDAC. Mechanistically, CASC8 interacted with c-Myc to enhance the stability of c-Myc protein, leading to the activation of the pentose phosphate pathway, a reduction of the NADP⁺/NADPH ratio and ultimately inhibiting disulfidptosis under glucose starvation conditions.</p><p><strong>Conclusions: </strong>This study provides evidence for the existence of disulfidptosis in PDAC and reveals the upregulation of CASC8 in this malignancy. Furthermore, we demonstrate that CASC8 acts as a crucial regulator of the pentose phosphate pathway and disulfidptosis, thereby promoting PDAC progression.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"26"},"PeriodicalIF":11.4,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048451","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":"GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradation.","authors":"Yikai Shen, Jie Lin, Tianlu Jiang, Xusheng Shen, Ying Li, Yiwang Fu, Penghui Xu, Lang Fang, Zetian Chen, Hongxin Huang, Yiwen Xia, Zekuan Xu, Linjun Wang","doi":"10.1186/s13046-025-03288-9","DOIUrl":"10.1186/s13046-025-03288-9","url":null,"abstract":"<p><strong>Background: </strong>Exosomes, as extracellular membrane vesicles, play important roles in intercellular communication and can influence tumour progression. Circular RNAs (circRNAs) have been reported in various malignancies and are also important components of exosomes. However, the role of exosomal circRNAs in gastric cancer (GC) progression has not been completely clarified.</p><p><strong>Methods: </strong>The exosomal circRNAs enriched in GC were identified using exosomal circRNA sequencing. The biological function of circMAN1A2 in GC was investigated using a series of in vitro and in vivo experiments. PKH-67 staining was used to label the exosomes. The molecular mechanism of exosomal circMAN1A2 was investigated via mass spectrometry, immunoprecipitation, Western blot, and single-cell RNA-sequencing data analyses.</p><p><strong>Results: </strong>In our study, we determined that circMAN1A2 (hsa_circ_0000118) was enriched in GC-derived exosomes. Higher circMAN1A2 expression was related to poor survival in GC patients (HR = 2.917, p = 0.0120). Exosomal circMAN1A2 promoted GC progression in vitro and in vivo and suppressed the antitumour activity of T cells. Moreover, circMAN1A2 bound to SFPQ in GC cells and T cells, promoting the G1/S phase transition of the cell cycle in GC cells while inhibiting the activation of the T cell receptor signalling pathway in T cells to decrease antitumour activity. Mechanistically, circMAN1A2 competed with FBXW11 for binding to SFPQ, preventing FBXW11-mediated k48-linked ubiquitination and SFPQ protein degradation, thereby stabilizing SFPQ expression.</p><p><strong>Conclusions: </strong>Our work confirms the critical role of exosomal circMAN1A2 in the progression and immunosuppression of GC. This novel axis of circMAN1A2-SFPQ provides new insights into exosomal circRNA-based GC diagnostic and therapeutic strategies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"24"},"PeriodicalIF":11.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043272","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: ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer.","authors":"Pingping Su, Xiaodan Mao, Jincheng Ma, Lixiang Huang, Lirui Yu, Shuting Tang, Mingzhi Zhuang, Zhonglei Lu, Kelvin Stefan Osafo, Yuan Ren, Xinrui Wang, Xite Lin, Leyi Huang, Xiaoli Huang, Elena Ioana Braicu, Jalid Sehouli, Pengming Sun","doi":"10.1186/s13046-025-03292-z","DOIUrl":"10.1186/s13046-025-03292-z","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"23"},"PeriodicalIF":11.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043270","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":"LLT1 overexpression renders allogeneic-NK resistance and facilitates the generation of enhanced universal CAR-T cells.","authors":"Shuxian Zhu, Shiyu Zuo, Chuo Li, Xingjie You, Erlie Jiang, Xiaoming Feng, Yuechen Luo","doi":"10.1186/s13046-025-03273-2","DOIUrl":"10.1186/s13046-025-03273-2","url":null,"abstract":"<p><strong>Background: </strong>The benefit of universal CAR-T cells over autologous CAR-T cell therapy is that they are a treatment that is ready to use. However, the prevention of graft-versus-host disease (GVHD) and host-versus-graft reaction (HVGR) remains challenging. Deleting class I of human leukocyte antigen (HLA-I) and class II of human leukocyte antigen (HLA-II) can prevent rejection by allogeneic T cells; however, natural killer (NK) cell rejection due to the loss of self-recognition remains unresolved. This study tested whether the overexpression of Lectin-like transcript 1 (LLT1), an NK cell inhibitory ligand, in T cell receptor (TCR) and HLA-I/II disrupted universal CD38-targeting CAR-T cells could prevent rejection by allogeneic NK cells.</p><p><strong>Methods: </strong>We generated CD38-targeting universal CAR-T cells by transducing T cells with lentiviruses encoding the CD38 CAR and LLT1 constructs. T cells were subjected to CD38, TCR, HLA-I, and HLA-II gene knockdown using CRISPR/Cas9, followed by lentiviral transduction. We performed cytotoxicity, proliferation, and cytokine assays to evaluate the functionality of universal chimeric antigen receptor-T cell (UCAR-T) cells and conducted in vitro and in vivo assays, including allogeneic responses and RNA sequencing, to assess their resistance to allogeneic T and NK cells, anti-leukemia efficacy, and persistence in treating hematologic malignancies.</p><p><strong>Results: </strong>Genetic editing of CD38 universal CAR-T cells, including CD38, T cell receptor alpha constant (TRAC), beta-2-microglobulin (B2M), and class II major histocompatibility complex transactivator (CIITA) knockdowns, was successfully achieved. In vitro, LLT1 overexpression boosted CAR-T cell proliferation and antitumor activity, leading to a transcriptional signature characterized by elevated stemness-related markers (SELL, BCL6, TCF7, and CD27) and increased levels of IL-10 and other cytokines. It also effectively mitigates rejection by allogeneic NK and T cells. In a humanized T-cell acute lymphoblastic leukemia (T-ALL) model, CD38 allogeneic universal CAR-T cells demonstrated superior survival rates and tumor clearance with reduced inflammatory responses.</p><p><strong>Conclusion: </strong>According to these results, LLT1 overexpression enhances UCAR-T cell activity and prevents allogeneic rejection, providing essential insights for the development of universal CAR-T cell therapy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"25"},"PeriodicalIF":11.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043276","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":"GPR137-RAB8A activation promotes ovarian cancer development via the Hedgehog pathway.","authors":"Chao Tang, Lin Li, Chongying Zhu, Qiang Xu, Zihao An, Shouying Xu, Chao Lin","doi":"10.1186/s13046-025-03275-0","DOIUrl":"10.1186/s13046-025-03275-0","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer (OC) progression is one of the commonest cause of female cancer death. While treatments in clinic includes primary surgery and targeted chemotherapy, curative and survival trends in OC have not significantly improved. Thus, further investigation of the mechanisms regarding OC carcinogenesis and discovery of novel targets is of great importance.</p><p><strong>Methods: </strong>Human ovarian tissue specimens, RNA sequencing, GEPIA database and bioinformatics analyses were used to analyze the gene correlation, and to identify and validate potential downstream candidates. The biological effects of GPR137-RAB8A-Hedgehog(HH) were investigated using in vitro and in vivo models and methods including qRT-PCR, RNA stability assay, RNA immunoprecipitation assay, GLI-luciferase reporter assay, nucleo-cytoplasmic separation assay, membrane-cytoplasmic separation assay, western blot, co-immunoprecipitation, immunofluorescence staining, cell counting kit-8 assay, wound healing assay, matrigel invasion assay, colony formation assay, xenografts assay, in situ transplantation tumor model of ovarian cancer in nude mice, and immunohistochemistry staining.</p><p><strong>Results: </strong>GPR137 expression was significantly higher in collected clinical OC tissues, compared with the adjacent normal tissues. Consistently, suppression of GPR137 inhibited human SK-OV-3 and A2780 OC cell proliferation, migration, invasion, and colony formation, whereas overexpression of GPR137 in human OC HO8910 cell exerted the opposite effects on cell biological behaviors. Mechanistically, RAB8A was identified as a downstream target of GPR137, and GPR137 promotes RAB8A expression by promoting RAB8A mRNA stability. By RNA-sequencing and experiments in vitro using multiple ovarian cancer cell models as well as in vivo using subcutaneous xenografts assay and in situ transplantation ovarian cancer model in nude mice, we further demonstrated that RAB8A positively mediated OC progression through activating HH signaling pathway by disassociating the protein-protein complex formation of GLI and SuFu (Suppressor of Fused), which reciprocally enhanced GPR137 activity, forming a regulation loop between HH signaling and GPR137.</p><p><strong>Conclusions: </strong>Collectively, this study depicts the role of GPR137-RAB8A-HH cascade in the development of OC, deepening our understanding of tumor biomechanics regarding OC progression and providing novel targets for OC therapy in future.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"22"},"PeriodicalIF":11.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043274","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":"Stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibition.","authors":"Mie K Jakobsen, Sofie Traynor, Aaraby Y Nielsen, Christina Dahl, Mette Staehr, Simon T Jakobsen, Maria S Madsen, Rasmus Siersbaek, Mikkel G Terp, Josefine B Jensen, Christina B Pedersen, Anup Shrestha, Jonathan R Brewer, Pascal H G Duijf, Odd L Gammelgaard, Henrik J Ditzel, Alexei F Kirkin, Per Guldberg, Morten F Gjerstorff","doi":"10.1186/s13046-025-03294-x","DOIUrl":"10.1186/s13046-025-03294-x","url":null,"abstract":"<p><strong>Background: </strong>Despite promising preclinical studies, the application of DNA methyltransferase inhibitors in treating patients with solid cancers has thus far produced only modest outcomes. The presence of intratumoral heterogeneity in response to DNA methyltransferase inhibitors could significantly influence clinical efficacy, yet our understanding of the single-cell response to these drugs in solid tumors remains very limited.</p><p><strong>Methods: </strong>In this study, we used cancer/testis antigen genes as a model for methylation-dependent gene expression to examine the activity of DNA methyltransferase inhibitors and their potential synergistic effect with histone deacetylase inhibitors at the single-cancer cell level. The analysis was performed on breast cancer patient-derived xenograft tumors and cell lines, employing a comprehensive set of techniques, including targeted single-cell mRNA sequencing. Mechanistic insights were further gained through DNA methylation profiling and chromatin structure analysis.</p><p><strong>Results: </strong>We show that breast cancer tumors and cell cultures exhibit a highly heterogenous response to DNA methyltransferase inhibitors, persisting even under high drug concentrations and efficient DNA methyltransferase depletion. The observed variability in response to DNA methyltransferase inhibitors was independent of cancer-associated aberrations and clonal genetic diversity. Instead, these variations were attributed to stochastic demethylation of regulatory CpG sites and the DNA methylation-independent suppressive function of histone deacetylases.</p><p><strong>Conclusions: </strong>Our findings point to intratumoral heterogeneity as a limiting factor in the use of DNA methyltransferase inhibitors as single agents in treatment of solid cancers and highlight histone deacetylase inhibitors as essential partners to DNA methyltransferase inhibitors in the clinic.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"21"},"PeriodicalIF":11.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11755921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025662","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":"TREM2 promotes the formation of a tumor-supportive microenvironment in hepatocellular carcinoma.","authors":"Hanrui Guo, Meiling Wang, Caiya Ni, Chun Yang, Chunxue Fu, Xiaoman Zhang, Xueling Chen, Xiangwei Wu, Jun Hou, Lianghai Wang","doi":"10.1186/s13046-025-03287-w","DOIUrl":"10.1186/s13046-025-03287-w","url":null,"abstract":"<p><strong>Background: </strong>Triggering receptor expressed on myeloid cells 2 (TREM2), a surface receptor predominantly expressed on myeloid cells, is a major hub gene in pathology-induced immune signaling. However, its function in hepatocellular carcinoma (HCC) remains controversial. This study aimed to evaluate the role of TREM2 in the tumor microenvironment in the context of HCC progression.</p><p><strong>Methods: </strong>HCC was experimentally induced in wild-type (WT) and Trem2-deficient (Trem2^-/-) mice, and clinical sample analysis and in vitro studies on macrophages were conducted. HCC cells were treated with conditioned medium from WT or Trem2^-/- macrophages, and their malignant phenotypes and underlying mechanisms were analyzed.</p><p><strong>Results: </strong>TREM2 deficiency reduced liver tumor burden in orthotopic and subcutaneous HCC models by altering CD8⁺ T cell infiltration. Trem2-deficient macrophages presented increased chemokine secretion. TGF-β1 was found to be positively correlated with TREM2 expression in HCC, and TGF-β blockade reversed TREM2 induction. On the other hand, TREM2⁺ macrophages were found to be associated with glycolysis and PKM2 expression in HCC cells; this association may be related to the secretion of IL-1β, which enhances the malignant phenotypes of HCC cells.</p><p><strong>Conclusions: </strong>These results reveal that TREM2⁺ macrophages play a driving role in HCC progression by suppressing CD8⁺ T cell infiltration and promoting tumor cell glycolysis, providing a new therapeutic target for HCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"20"},"PeriodicalIF":11.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015375","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}