Cancer gene therapy最新文献

{"title":"Long non-coding RNA PRSS23-AS1 as ceRNA promotes breast cancer progression by regulating EMT via miR-3176 /YBX1 axis.","authors":"Yun Huang, Mudan Feng, Yiwei Jiang, Maihuan Wang, Mingkun Wang, Zhen Cao","doi":"10.1038/s41417-025-00943-3","DOIUrl":"https://doi.org/10.1038/s41417-025-00943-3","url":null,"abstract":"<p><p>Breast cancer (BC) remains a leading cause of cancer-related mortality, largely due to its aggressive proliferation and metastatic potential. Long non-coding RNAs (lncRNAs) have emerged as key regulators in tumor development and progression. This study explored the functional role and mechanism of Lnc-PRSS23-AS1 in BC. We assessed Lnc-PRSS23-AS1 expression and localization using fluorescence in situ hybridization, qRT-PCR, and Western blotting in BC tissues and cell lines. Binding interactions between Lnc-PRSS23-AS1, miR-3176, and Y-box binding protein 1 (YBX1) were validated through dual-luciferase reporter assays, RNA pulldown, and RNA immunoprecipitation. Lnc-PRSS23-AS1 was significantly upregulated in BC and predominantly localized in the cytoplasm. Silencing Lnc-PRSS23-AS1 or overexpressing miR-3176 suppressed BC cell proliferation, migration, and invasion in vitro and in vivo. Conversely, miR-3176 inhibition or YBX1 overexpression reversed these effects. Mechanistically, Lnc-PRSS23-AS1 promoted YBX1 protein expression by acting as a molecular sponge for miR-3176. These findings highlight the Lnc-PRSS23-AS1/miR-3176/YBX1 axis as a driver of BC progression and suggest Lnc-PRSS23-AS1 as a potential therapeutic target for breast cancer treatment.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapamycin rescues APC-mutated colon organoid differentiation.","authors":"Aline Habib, Rose Mamistvalov, Dalit Ben-Yosef","doi":"10.1038/s41417-025-00935-3","DOIUrl":"https://doi.org/10.1038/s41417-025-00935-3","url":null,"abstract":"<p><p>Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by germline mutations in the adenomatous polyposis coli (APC) gene. This leads to numerous colorectal adenomas and a high risk of colorectal cancer (CRC). Our stem cell-derived colon organoid model revealed that a heterozygous APC mutation is sufficient to induce colorectal cancer formation. We found a link between APC mutation type, organoid maturation and FAP severity. Here, we show that severe germline mutations in hESCs employ diverse mechanisms of carcinogenesis. FAP1-hESCs expressing a truncated 332-amino acid protein exhibited a hyperactivated mTOR pathway, including PTEN inactivation and increased S6K1 and eIF4E activation. This affected oncogenic c-Myc expression and contributed to apoptosis resistance. Rapamycin treatment restored differentiation potential in FAP1 organoids but not FAP2 organoids, which expressed a larger truncated protein without mTOR pathway activation. Our in vitro colon organoids system findings were validated in human patients. Notably, a colon from a FAP1 patient exhibited high expression of mTOR pathway proteins. These findings highlight the potential of rapamycin for personalized therapy in FAP patients with distinct mTOR-mediated APC mutations. Our colon organoid model is valuable for studying CRC and developing new diagnostic, preventive, and therapeutic approaches to prevent or delay tumorigenesis in FAP patients.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting colorectal cancer risk in FAP patients using patient-specific organoids.","authors":"Aline Habib, Rose Mamistvalov, Mira Malcov, Dalit Ben-Yosef","doi":"10.1038/s41417-025-00923-7","DOIUrl":"https://doi.org/10.1038/s41417-025-00923-7","url":null,"abstract":"<p><p>Colorectal cancer (CRC), a prevalent global cancer, is mostly sporadic. Familial adenomatous polyposis (FAP), arises from APC germline mutations. We established FAP-human embryonic stem cell lines (FAP1,2,3) with distinct APC mutations and differentiated them into colon organoids to study cancer development. While normal expressing APC lines and FAP3 formed complex organoids, FAP1,2 failed to differentiate. By utilizing CRISPR editing to correct APC mutations in FAP1,2, we succeeded in restoring their ability to form complex organoids expressing colon gene (CDX2). To elucidate the truncated APC proteins' mechanism of action, we used AlphaFold2 algorithm to model their secondary structures. Structural analysis of the normal phenotype organoids (normal and FAP3) revealed 5-6 salt bridges only at the N-terminal oligomerization domain. In contrast, analysis of disease organoids-phenotype (FAP1,2) revealed a production of novel salt bridges, likely act in a dominant-negative manner on full-length APC, disrupting APC function and promoting tumorigenesis. Our study underscores the critical role of germline APC mutations in colon cancer initiation, revealing how specific mutations influence disease severity. By deciphering APC structure-function relationships, we illuminate potential therapies and the molecular underpinnings of APC mutations that precede clinical presentation.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-intrinsic platinum response and associated genetic and gene expression signatures in ovarian cancer.","authors":"Kristin M Adams, Jae-Rim Wendt, Josie Wood, Sydney Olson, Ryan Moreno, Zhongmou Jin, Srihari Gopalan, Jessica D Lang","doi":"10.1038/s41417-025-00941-5","DOIUrl":"10.1038/s41417-025-00941-5","url":null,"abstract":"<p><p>Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making. Previous work has relied on poor models of the most common subtypes of epithelial ovarian cancers and necessitates a careful examination of the most suitable in vitro models. We performed extensive drug dose response assays and gene expression profiling on 36 ovarian cancer cell lines across over seven subtypes. This is the largest quantitative database of quantitative cisplatin and carboplatin response in ovarian cancer cell lines. Our results demonstrate that cell lines largely fall either well above or below the clinical maximally achievable dose (C_max) of each compound. We performed differential expression analysis for high-grade serous ovarian carcinoma cell lines. Further, we generated two platinum-resistant derivatives each for OVCAR3 and OVCAR4. Combined with clinically resistant PEO1/PEO4/PEO6 and PEA1/PEA2 isogenic models, we performed differential expression analysis for seven platinum-resistant isogenic pairs. Common themes in differential expression were innate immunity/STAT activation, epithelial-to-mesenchymal transition (EMT) and stemness, and platinum influx/efflux regulators. We also performed copy number signature analysis and orthogonal measures of homologous recombination deficiency (HRD) scar scores and copy number burden, which is the first report to our knowledge applying field-standard copy number signatures to ovarian cancer cell lines. We also examined markers and functional readouts of stemness that revealed that cell lines are poor models for examination of stemness contributions to platinum resistance, suggesting that this is a transient state. Overall, this study serves as a resource to determine the best cell lines to utilize for ovarian cancer research on certain subtypes and platinum response studies, as well as sparks new hypotheses for future study in ovarian cancer.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated multidimensional bioinformatics analysis of the molecular mechanisms of ulcerative colitis-associated colorectal cancer and MMP1 as a potential therapeutic target.","authors":"Xiaopeng Yu, Yutian Tang, Junjie Niu, Jinyang Hu","doi":"10.1038/s41417-025-00917-5","DOIUrl":"https://doi.org/10.1038/s41417-025-00917-5","url":null,"abstract":"<p><p>This study aimed to investigate the molecular mechanisms underlying ulcerative colitis (UC)-associated colorectal cancer (CRC) development and identify potential therapeutic targets through integrated multi-omics analysis. Mendelian randomization (MR) analysis, combined with bioinformatics approaches including differential gene expression analysis, protein-protein interaction network construction, gene set enrichment analysis, and single-cell RNA sequencing, was employed. Data were obtained from GEO, TCGA, and genome-wide association study (GWAS) databases. Drug prediction and molecular docking were performed using DSigDB and AutoDockTools. A total of 48 shared genes were identified between UC and CRC, with MMP1 emerging as a significant protective factor (OR = 0.766; 95% CI = 0.593-0.989, P = 0.041). MMP1 demonstrated strong diagnostic potential (AUC = 0.927, 95% CI = 0.895-0.959) and was functionally associated with immune regulation and metabolic pathways. Single-cell analysis revealed predominant MMP1 expression in fibroblasts and immune cells, while immune infiltration analysis showed significant correlations with CD8⁺ T cells and NK cells. Mediation MR analysis indicated that 63.33% of MMP1's protective effect was mediated through naive-mature B cells. Drug prediction identified ilomastat as a potential MMP1 inhibitor with strong binding affinity (binding energy = -7.17 kcal/mol). These findings provide evidence for MMP1's protective role in UC-associated CRC through immune microenvironment modulation, highlighting its potential as a diagnostic biomarker and therapeutic target. The identification of ilomastat as a potential MMP1 inhibitor offers new avenues for targeted therapy in inflammation-associated cancers.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RUNX1A isoform is overexpressed in acute myeloid leukemia and is associated with FLT3 internal tandem duplications.","authors":"Cosimo Cumbo, Francesco Tarantini, Elisa Parciante, Luisa Anelli, Antonella Zagaria, Giuseppina Biondi, Mariano Francesco Caratozzolo, Paola Orsini, Nicoletta Coccaro, Giuseppina Tota, Immacolata Redavid, Maria Rosa Conserva, Angela Minervini, Crescenzio Francesco Minervini, Vito Pier Gagliardi, Mario Delia, Flaviana Marzano, Claudia Telegrafo, Sharon Natasha Cox, Annalisa Natalicchio, Bachir Balech, Apollonia Tullo, Mattia Gentile, Francesco Giorgino, Giorgina Specchia, Pellegrino Musto, Francesco Albano","doi":"10.1038/s41417-025-00939-z","DOIUrl":"https://doi.org/10.1038/s41417-025-00939-z","url":null,"abstract":"<p><p>RUNX1A is the shortest and least expressed of the RUNX1 three main isoforms (A, B, C); despite this, the leukemogenic role of its overexpression has been clearly described. Several studies have shown RUNX1A involvement in different blood cancers and pilot observations in acute leukemia have been reported. In this context, we evaluated RUNX1 isoforms expression in a cohort of acute myeloid leukemia (AML) patients, finding overexpression of RUNX1A and RUNX1B, with higher median levels in thrombocytopenic cases. No difference was observed for RUNX1C. RUNX1A overexpression is higher in more immature AML phenotypes. According to the mutational profile, FLT3 internal tandem duplication (ITD) positive cases have the highest RUNX1A levels and the presence of FLT3-ITD was the only molecular variable able to influence RUNX1A expression. RUNX1A overexpression is disease-related, associated with a specific transcriptional profile, and reappears at relapse, with no clear kinetics except in FLT3-ITD cases. Overall, we demonstrate RUNX1A overexpression in AML and its association with the FLT3-ITD molecular subtype. Our data shed light on the dark side of RUNX1 deregulation, paving the way for further investigations.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE deficiency triggers anti-tumour activity of macrophages in liver cancer.","authors":"Xintong Xia, Zijun Zhou, Xiaoxiao Zheng, Chaoyong Tu, Hao Liu, Zhiming Hu, Tao Ma, Yuexiao Tang, Wei Chen","doi":"10.1038/s41417-025-00936-2","DOIUrl":"https://doi.org/10.1038/s41417-025-00936-2","url":null,"abstract":"<p><p>Macrophage infiltration correlates with poor prognosis in patients with liver cancer and resistance to immunotherapy. However, it is difficult to target tumour-associated macrophages (TAMs) because of their inherent heterogeneity. Specific TAM subsets may exhibit distinct functions in tumorigenesis. Herein, we identify a TAM subset characterised by elevated APOE expression, which is correlated with poor overall survival of patients with HCC. The APOE⁺ TAM intensity is highly elevated in ICB non-responder tumours and negatively correlated with CD8⁺ T cell infiltration. Pathway analysis and cell interaction reveal that APOE⁺ TAMs suppress CD8⁺ T cells through signal integration and cholesterol efflux. Furthermore, APOE deficiency in macrophages delays tumour growth and promotes the infiltration of CD8⁺ T cells. Using an immunotherapy-resistant mouse model, we showed that APOE blockade synergises with anti-PD-1 therapy and inhibits tumour growth. Our results elucidate the crucial role of APOE⁺ TAMs in the formation of immunosuppressive microenvironments and offer a potential therapeutic target for ICB combined therapy.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM).","authors":"Filipa Martins, Renata Arada, Hélio Barros, Paulo Matos, José Ramalho, Valentín Ceña, Vasco D B Bonifácio, Luís G Gonçalves, Jacinta Serpa","doi":"10.1038/s41417-025-00933-5","DOIUrl":"https://doi.org/10.1038/s41417-025-00933-5","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting mTORC2 in lung squamous cell carcinoma improves anti-tumor immunity through the PSGL-1-VISTA axis.","authors":"Verra M Ngwa, Yoonha Hwang, Wenqiang Song, Deanna N Edwards, Jin Chen","doi":"10.1038/s41417-025-00934-4","DOIUrl":"https://doi.org/10.1038/s41417-025-00934-4","url":null,"abstract":"<p><p>Targeted therapies have improved survival for lung adenocarcinoma patients. However, similar advances are lacking for lung squamous carcinoma (LUSC). Advances in immunotherapy have shown some promise, but the overall response rate remains low in LUSC. Here, we demonstrate that the mTORC2 signaling pathway represents an actionable target in LUSC to improve anti-tumor immune responses. We show that genetic alterations affecting the mTORC2 pathway are common among patients with LUSC tumors, and targeting mTORC2 reduces LUSC tumor growth in mouse models. Transcriptomics reveal that mTORC2-deficient LUSC cells exhibit reduced expression of glycolytic and hypoxia-related genes. In agreement, loss of mTORC2 signaling decreases lactate levels in tumor-interstitial fluid, creating reduced acidity within the tumor microenvironment. Interestingly, mTORC2-deficient LUSC cells also exhibited reduced expression of the pH-sensitive VISTA ligand PSGL-1 in a HIF-2α dependent mechanism. LUSC patients, but not those with LUAD, display a positive correlation in expression between HIF-2α and PSGL-1, suggesting a distinct association among mTORC2, HIF-2α, and immune responses in LUSC. Indeed, mTORC2 loss-of-function enhanced CD8⁺ T cell activation in tumors, while use of anti-VISTA immunotherapy reduced LUSC tumor burden only in the presence of intact mTORC2 signaling. Collectively, these data describe an important role of mTORC2 signaling in LUSC tumors and demonstrate the therapeutic potential of targeting the mTORC2/PSGL-1/VISTA axis in patients that are non-responsive to current therapies.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DR1 activates histone gene expression to maintain pancreatic cancer cell survival through the ATAC complex.","authors":"Ziwei Guo, XiangZheng Liu, Mo Chen","doi":"10.1038/s41417-025-00938-0","DOIUrl":"https://doi.org/10.1038/s41417-025-00938-0","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is the most malignant cancer and is characterized by short survival and limited treatment options. Epigenetic dysregulation is a defining feature of tumorigenesis but remains elusive in PDAC. Here, we identified DR1 as a vulnerability in PDAC. Loss of DR1 inhibited PDAC cell survival through repressing cell cycle. Mechanistically, DR1 recruited the ATAC complex to histone promoter regions to acetylate H3K9 and subsequently activate the expression of histone genes, ultimately promoting cell cycle and maintaining PDAC cell survival. Moreover, we uncovered a positive correlation between histone gene expression and the survival of patients with PDAC. In conclusion, our findings underscore the pivotal role of DR1 in the regulation of histone genes through the ATAC complex, providing a potential therapeutic target for PDAC.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}