The epithelial-to-mesenchymal transition (EMT) is a pivotal cellular process integral to metastasis. Emerging evidence indicates that EMT progresses through a continuum of cellular states, yet the intricate regulatory mechanisms underpinning this transition are not fully elucidated. This study aims to reconstruct the EMT spectrum in lung adenocarcinoma (LUAD) by integrating single-cell RNA sequencing data with advanced cell trajectory inference techniques. We identified five distinct EMT states across 16,310 malignant epithelial cells derived from 10 LUAD patients, encompassing epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M) phenotypes. Notably, the hybrid E/M states exhibited the highest metastatic potential and were correlated with a poorer prognosis for patients. By modeling the EMT regulatory network, we evaluated the influence of transcription factor (TF) activation on network stability during cellular state transitions. We identified critical TFs, including TCF7, FOXA1, FOXA2, and SMAD7, which collectively regulate pathways such as TGF-β through both intrinsic EMT-related signaling and the modulation of tumor-associated macrophages. Furthermore, we developed a risk stratification model based on EMT continuum signatures, providing a novel tool for prognostic assessment. Our findings contribute to a comprehensive understanding of EMT-driven tumor evolution and open new avenues for prognostic stratification and targeted therapies in LUAD.
{"title":"Construction of the cancer cell continuum reveals hybrid EMT state driving lung adenocarcinoma aggression.","authors":"Qiuhao Qu, Yixin Ma, Chao Huang, Botao Fa, Zhenni Liu, Yuhan Li, Shigao Yang, Zhengtao Xiao","doi":"10.1038/s41417-025-00991-9","DOIUrl":"https://doi.org/10.1038/s41417-025-00991-9","url":null,"abstract":"<p><p>The epithelial-to-mesenchymal transition (EMT) is a pivotal cellular process integral to metastasis. Emerging evidence indicates that EMT progresses through a continuum of cellular states, yet the intricate regulatory mechanisms underpinning this transition are not fully elucidated. This study aims to reconstruct the EMT spectrum in lung adenocarcinoma (LUAD) by integrating single-cell RNA sequencing data with advanced cell trajectory inference techniques. We identified five distinct EMT states across 16,310 malignant epithelial cells derived from 10 LUAD patients, encompassing epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M) phenotypes. Notably, the hybrid E/M states exhibited the highest metastatic potential and were correlated with a poorer prognosis for patients. By modeling the EMT regulatory network, we evaluated the influence of transcription factor (TF) activation on network stability during cellular state transitions. We identified critical TFs, including TCF7, FOXA1, FOXA2, and SMAD7, which collectively regulate pathways such as TGF-β through both intrinsic EMT-related signaling and the modulation of tumor-associated macrophages. Furthermore, we developed a risk stratification model based on EMT continuum signatures, providing a novel tool for prognostic assessment. Our findings contribute to a comprehensive understanding of EMT-driven tumor evolution and open new avenues for prognostic stratification and targeted therapies in LUAD.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145602516","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}
Pub Date : 2025-11-24DOI: 10.1038/s41417-025-00990-w
Yaxin Zhang, Liping Yan, Na An, Jiayu Geng, Wei Zhao, Bohao Feng, Yanlong Zheng, Shaojun Liang, Lei Yang
Cisplatin resistance causes ineffectiveness of cisplatin-based treatment for cervical carcinoma. The combination of cisplatin and other chemotherapeutic drugs is an available strategy to overcome this problem. However, chemotherapeutic drugs combined with cisplatin may show tissue toxicity and systemic side effects. Thus, there is a great need of seeking effective substitutes for these chemotherapeutic drugs to improve combination therapy. Here, we found that inactivating IL-6/JAK2/STAT3 signaling pathway sensitized carcinoma cells to cisplatin toxicity by increasing cisplatin accumulation, impairing DNA damage repair, and inhibiting the initiation and development of autophagy, which subsequently caused the increases in DNA damage levels and apoptosis rates in cisplatin-treated cells. We predicted that TFF3 negatively regulated transduction in the IL-6/JAK2/STAT3 pathway based on in silico analysis of the differentially expressed genes (DEGs) between highly trefoil factor 3(TFF3)-encoding mRNA-expressing carcinoma tissues and low-expressing counterparts, and experimentally determined that both ectopic expression of TFF3-encoding gene and TFF3 administration inhibited IL-6-induced STAT3 activation in carcinoma cells. Mechanistically, upon binding to IGF2R, TFF3 stabilized IGF2R by inhibiting the ubiquitin-proteasome degradation pathway to inactivate Akt and thereby STAT3. Moreover, we discovered that TFF3 administration antagonized protective effects of IL-6 stimulation against tumor-killing capacity of cisplatin. Based on these findings, we consider that TFF3 may be employed as a cisplatin sensitizer and have advantages over traditional chemotherapeutic drugs in cisplatin-based combination therapy, since it is a naturally occurring protein in cervical tissue.
{"title":"TFF3 sensitizes cervical carcinoma cells to cisplatin toxicity by binding to IGF2R","authors":"Yaxin Zhang, Liping Yan, Na An, Jiayu Geng, Wei Zhao, Bohao Feng, Yanlong Zheng, Shaojun Liang, Lei Yang","doi":"10.1038/s41417-025-00990-w","DOIUrl":"10.1038/s41417-025-00990-w","url":null,"abstract":"Cisplatin resistance causes ineffectiveness of cisplatin-based treatment for cervical carcinoma. The combination of cisplatin and other chemotherapeutic drugs is an available strategy to overcome this problem. However, chemotherapeutic drugs combined with cisplatin may show tissue toxicity and systemic side effects. Thus, there is a great need of seeking effective substitutes for these chemotherapeutic drugs to improve combination therapy. Here, we found that inactivating IL-6/JAK2/STAT3 signaling pathway sensitized carcinoma cells to cisplatin toxicity by increasing cisplatin accumulation, impairing DNA damage repair, and inhibiting the initiation and development of autophagy, which subsequently caused the increases in DNA damage levels and apoptosis rates in cisplatin-treated cells. We predicted that TFF3 negatively regulated transduction in the IL-6/JAK2/STAT3 pathway based on in silico analysis of the differentially expressed genes (DEGs) between highly trefoil factor 3(TFF3)-encoding mRNA-expressing carcinoma tissues and low-expressing counterparts, and experimentally determined that both ectopic expression of TFF3-encoding gene and TFF3 administration inhibited IL-6-induced STAT3 activation in carcinoma cells. Mechanistically, upon binding to IGF2R, TFF3 stabilized IGF2R by inhibiting the ubiquitin-proteasome degradation pathway to inactivate Akt and thereby STAT3. Moreover, we discovered that TFF3 administration antagonized protective effects of IL-6 stimulation against tumor-killing capacity of cisplatin. Based on these findings, we consider that TFF3 may be employed as a cisplatin sensitizer and have advantages over traditional chemotherapeutic drugs in cisplatin-based combination therapy, since it is a naturally occurring protein in cervical tissue.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 1","pages":"155-168"},"PeriodicalIF":5.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595723","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}
Pub Date : 2025-11-24DOI: 10.1038/s41417-025-00987-5
Jeremy A Bravo Narula, Kasturee Jagirdar, Sumaiya Begum, Kuai Yu, Meihan Wei, Bailey Roberson, Marie Portuallo, Limin An, Steffanus Hallis, Viviana A Smart, Manoel O Moraes Junior, Qin Liu, Hongkai Ji, Vito W Rebecca
Acral melanoma (AM), a rare and aggressive subtype with 5-year survival rates below 16%, exhibits limited response to CDK4/6 inhibitors (CDK4i/6i) despite frequent pathway alterations. Here, we identify AKT-mTOR signaling as a critical escape mechanism triggered by CDK4/6 inhibition. Using a genetically diverse panel of AM cell lines, we demonstrate that CDK4i/6i induces rapid hyperactivation of AKT (pS473) and mTORC1 (pS6 S240/244) alongside Rb dephosphorylation. Interestingly, CDK4i/6i disrupts the cytoplasmic interaction of Rb with the mTORC2 subunit Sin1, suggesting the loss of the Rb-Sin1 protein-protein interaction may lead to mTORC2-mediated AKT hyperactivation following CDK4i/6i. Pharmacological inhibition of the AKT-mTOR axis significantly increases CDK4i/6i efficacy, as seen in the ability to reduce clonogenic survival and the ability to increase annexin+ cytotoxicity relative to single-agent CDK4i/6i, AKTi, or mTORi activity alone. These findings provide preclinical rationale for co-targeting CDK4/6 and mTORC1/2 to improve AM outcomes.
{"title":"mTORC1/2 inhibition induces tumor regression in CDK4/6 inhibitor-insensitive acral melanoma.","authors":"Jeremy A Bravo Narula, Kasturee Jagirdar, Sumaiya Begum, Kuai Yu, Meihan Wei, Bailey Roberson, Marie Portuallo, Limin An, Steffanus Hallis, Viviana A Smart, Manoel O Moraes Junior, Qin Liu, Hongkai Ji, Vito W Rebecca","doi":"10.1038/s41417-025-00987-5","DOIUrl":"https://doi.org/10.1038/s41417-025-00987-5","url":null,"abstract":"<p><p>Acral melanoma (AM), a rare and aggressive subtype with 5-year survival rates below 16%, exhibits limited response to CDK4/6 inhibitors (CDK4i/6i) despite frequent pathway alterations. Here, we identify AKT-mTOR signaling as a critical escape mechanism triggered by CDK4/6 inhibition. Using a genetically diverse panel of AM cell lines, we demonstrate that CDK4i/6i induces rapid hyperactivation of AKT (pS473) and mTORC1 (pS6 S240/244) alongside Rb dephosphorylation. Interestingly, CDK4i/6i disrupts the cytoplasmic interaction of Rb with the mTORC2 subunit Sin1, suggesting the loss of the Rb-Sin1 protein-protein interaction may lead to mTORC2-mediated AKT hyperactivation following CDK4i/6i. Pharmacological inhibition of the AKT-mTOR axis significantly increases CDK4i/6i efficacy, as seen in the ability to reduce clonogenic survival and the ability to increase annexin<sup>+</sup> cytotoxicity relative to single-agent CDK4i/6i, AKTi, or mTORi activity alone. These findings provide preclinical rationale for co-targeting CDK4/6 and mTORC1/2 to improve AM outcomes.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595734","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}
Despite significant advancements in diagnosis and treatment, cancer remains a leading cause of mortality globally. Cancer gene therapy has emerged as a promising strategy, with numerous clinical trials demonstrating its efficacy in targeting tumor cells, vasculature, and immune components. However, precise and selective gene expression regulation remains a challenge. In this study, we demonstrated that the CREPT (cell-cycle related and expression-elevated protein in tumor) promoter holds great potential for targeted cancer gene therapy. CREPT, a tumor-promoting protein as a positive regulator of gene transcription, is highly expressed across various cancer types while exhibiting minimal expression in normal tissues. The CREPT promoter mediated robust and tumor-selective transgene expression in vivo following both local and systemic administration, with only minimal off-target expression detected in blood and none in normal organs. Leveraging this specificity, we engineered an adenovirus encoding diphtheria toxin fragment A under CREPT promoter regulation. This construct was selectively expressed and inhibited protein synthesis, leading cancer cell death in vitro and in vivo. These findings demonstrate that the CREPT promoter may serve as a useful regulatory element for the development of targeted cancer gene therapy.
尽管在诊断和治疗方面取得了重大进展，但癌症仍然是全球死亡的主要原因。癌症基因治疗已经成为一种很有前途的策略，大量的临床试验证明了它在靶向肿瘤细胞、脉管系统和免疫成分方面的有效性。然而，精确和选择性的基因表达调控仍然是一个挑战。在这项研究中，我们证明了肿瘤细胞周期相关和表达升高蛋白（cellular -cycle related and expression-elevated protein In tumor）启动子在靶向癌症基因治疗中具有很大的潜力。蹑手蹑脚是一种肿瘤促进蛋白，作为基因转录的正调节因子，在各种癌症类型中高表达，而在正常组织中表达很少。在局部和全身给药后，悄悄启动子介导了体内强大的肿瘤选择性转基因表达，仅在血液中检测到少量脱靶表达，在正常器官中未检测到脱靶表达。利用这种特异性，我们设计了一种在爬行启动子调控下编码白喉毒素片段A的腺病毒。该构建体在体外和体内选择性表达并抑制蛋白质合成，导致癌细胞死亡。这些发现表明，匍匐启动子可能作为一个有用的调控元件，开发靶向癌症基因治疗。
{"title":"Targeted suppression of tumor growth by CREPT promoter-driven diphtheria toxin fragment A","authors":"Jingya Li, Mengdi Li, Wenchen Wang, Guancheng Jiang, Yinyin Wang, Jianqiu Sheng, Zhijie Chang, Jian Sheng, Mingyang Li, Fangli Ren","doi":"10.1038/s41417-025-00961-1","DOIUrl":"10.1038/s41417-025-00961-1","url":null,"abstract":"Despite significant advancements in diagnosis and treatment, cancer remains a leading cause of mortality globally. Cancer gene therapy has emerged as a promising strategy, with numerous clinical trials demonstrating its efficacy in targeting tumor cells, vasculature, and immune components. However, precise and selective gene expression regulation remains a challenge. In this study, we demonstrated that the CREPT (cell-cycle related and expression-elevated protein in tumor) promoter holds great potential for targeted cancer gene therapy. CREPT, a tumor-promoting protein as a positive regulator of gene transcription, is highly expressed across various cancer types while exhibiting minimal expression in normal tissues. The CREPT promoter mediated robust and tumor-selective transgene expression in vivo following both local and systemic administration, with only minimal off-target expression detected in blood and none in normal organs. Leveraging this specificity, we engineered an adenovirus encoding diphtheria toxin fragment A under CREPT promoter regulation. This construct was selectively expressed and inhibited protein synthesis, leading cancer cell death in vitro and in vivo. These findings demonstrate that the CREPT promoter may serve as a useful regulatory element for the development of targeted cancer gene therapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 1","pages":"145-154"},"PeriodicalIF":5.0,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581965","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}
Pub Date : 2025-11-22DOI: 10.1038/s41417-025-00968-8
Chiao-Ping Chen, Tsai-Hsien Hung, Yenlin Huang, Yi-Ru Pan, Chun-Nan Yeh, Wen-Kuan Huang, Yu-Tien Hsiao, Chih-Hong Lo, Alice L. Yu, John Yu, Chiao-En Wu
Cholangiocarcinoma (CCA) exhibits poor prognosis despite recent advances in targeted therapy and immunotherapy. Therefore, uncovering novel mechanisms of CCA tumorigenesis and identifying effective targeted therapies are critical for improving treatment outcomes in advanced cases. PufA, a newly identified member of the Puf-family RNA-binding proteins and a biogenesis factor, is overexpressed in CCA and correlates with poor survival outcomes. Functional studies demonstrate that PufA silencing in CCA cell lines significantly reduces cell viability, induces apoptosis, and suppresses migration by inhibiting epithelial-mesenchymal transition (EMT). Additionally, PufA knockdown impairs sphere formation in vitro and inhibits tumor growth in xenograft mouse models. RNA sequencing analysis reveals significant downregulation of RELA encodes protein of p65, which encodes the p65 protein, a critical subunit for NFκB signaling activation, suggesting a connection between PufA and the NFκB signaling pathway. Mechanistic investigations confirm that PufA promotes IκBα degradation, thereby activating the NFκB signaling and regulating downstream cytokine expression, including IL1A. Conversely, PufA overexpression enhances IκBα degradation following TNFα stimulation in CCA cells, supporting the correlation between PufA and the NFκB signaling pathway. These findings establish PufA as a pivotal regulator of CCA progression and highlight the PufA-NFκB axis as a potential therapeutic target. This study provides critical insights into the molecular drivers of CCA and lays a foundation for developing novel treatments to enhance patient outcomes.
尽管最近在靶向治疗和免疫治疗方面取得了进展，但胆管癌（CCA）的预后较差。因此，揭示CCA肿瘤发生的新机制和确定有效的靶向治疗对于改善晚期病例的治疗效果至关重要。PufA是puf家族rna结合蛋白的新成员，也是一种生物发生因子，在CCA中过度表达，与较差的生存结果相关。功能研究表明，在CCA细胞系中，PufA沉默可显著降低细胞活力，诱导细胞凋亡，并通过抑制上皮-间质转化（epithelial-mesenchymal transition， EMT）抑制迁移。此外，PufA敲低可损害体外球体形成并抑制异种移植小鼠模型中的肿瘤生长。RNA测序分析显示，RELA编码p65蛋白显著下调，p65蛋白编码p65蛋白，p65蛋白是NFκB信号通路激活的关键亚基，这表明PufA与NFκB信号通路之间存在联系。机制研究证实，PufA促进i - κ b α降解，从而激活nf - κ b信号传导并调节下游细胞因子的表达，包括IL1A。相反，在CCA细胞中，PufA过表达增强TNFα刺激后i - κ b α的降解，支持PufA与nf - κ b信号通路之间的相关性。这些发现表明PufA是CCA进展的关键调节因子，并强调PufA- nfκ b轴是一个潜在的治疗靶点。这项研究为CCA的分子驱动因素提供了重要的见解，并为开发新的治疗方法奠定了基础，以提高患者的预后。
{"title":"PufA drives cholangiocarcinoma progression via NFκB signaling activation: a novel therapeutic target","authors":"Chiao-Ping Chen, Tsai-Hsien Hung, Yenlin Huang, Yi-Ru Pan, Chun-Nan Yeh, Wen-Kuan Huang, Yu-Tien Hsiao, Chih-Hong Lo, Alice L. Yu, John Yu, Chiao-En Wu","doi":"10.1038/s41417-025-00968-8","DOIUrl":"10.1038/s41417-025-00968-8","url":null,"abstract":"Cholangiocarcinoma (CCA) exhibits poor prognosis despite recent advances in targeted therapy and immunotherapy. Therefore, uncovering novel mechanisms of CCA tumorigenesis and identifying effective targeted therapies are critical for improving treatment outcomes in advanced cases. PufA, a newly identified member of the Puf-family RNA-binding proteins and a biogenesis factor, is overexpressed in CCA and correlates with poor survival outcomes. Functional studies demonstrate that PufA silencing in CCA cell lines significantly reduces cell viability, induces apoptosis, and suppresses migration by inhibiting epithelial-mesenchymal transition (EMT). Additionally, PufA knockdown impairs sphere formation in vitro and inhibits tumor growth in xenograft mouse models. RNA sequencing analysis reveals significant downregulation of RELA encodes protein of p65, which encodes the p65 protein, a critical subunit for NFκB signaling activation, suggesting a connection between PufA and the NFκB signaling pathway. Mechanistic investigations confirm that PufA promotes IκBα degradation, thereby activating the NFκB signaling and regulating downstream cytokine expression, including IL1A. Conversely, PufA overexpression enhances IκBα degradation following TNFα stimulation in CCA cells, supporting the correlation between PufA and the NFκB signaling pathway. These findings establish PufA as a pivotal regulator of CCA progression and highlight the PufA-NFκB axis as a potential therapeutic target. This study provides critical insights into the molecular drivers of CCA and lays a foundation for developing novel treatments to enhance patient outcomes.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 1","pages":"132-144"},"PeriodicalIF":5.0,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581984","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}
Pub Date : 2025-11-17DOI: 10.1038/s41417-025-00988-4
Cong Zhang, Yu Wang, Biao Xie
Thyroid cancer (TC) is an endocrine malignancy characterized by metabolic abnormalities, with its incidence continually on the rise. Understanding the pathogenesis of this cancer would help develop better diagnostic and therapeutic methods. We aimed to integrate single-cell transcriptomics, bulk transcriptomics, and GWAS data to identify causal associations with thyroid cancer at the gene level. We intended to utilize single-cell atlases to identify malignant cells and their characteristics, and employed SMR to search for genetic loci causally associated with thyroid cancer. We validated the expression differences of the genes at the single-cell level and bulk level, as well as through immunohistochemistry experimental results. We investigated the tumor immune microenvironment of patients, attempting to find immune subgroups with differential proportions. Based on these subgroups, we conducted multi-machine learning modeling to predict the likelihood of disease and developed a corresponding interactive web application. HMGA2, SDCCAG8, DLG5, MT1E, RABL2B, RERE, and NDUFA12 all demonstrated to varying degrees their roles in promoting or inhibiting the occurrence and development of thyroid cancer, with HMGA2 showing consistency across all analyses. We also identified some immune subtypes significantly associated with TC and chose markers of T_cell_C8_STMN1 to construct patient diagnostic models. Through various combinations of machine learning feature selection and model construction, we ultimately built 178 diagnostic models, with the combination of glmBoost+RF having the best diagnostic performance (Average AUPR: 0.9915). The predictive web pages ( https://zclab-cnp.shinyapps.io/TC-WEB/ ) can provide convenience and reference for clinical personnel.
{"title":"Meta single-cell atlas and xQTL post-GWAS analysis revealed the pathogenic features of thyroid cancer for target therapy: A multi-omics study","authors":"Cong Zhang, Yu Wang, Biao Xie","doi":"10.1038/s41417-025-00988-4","DOIUrl":"10.1038/s41417-025-00988-4","url":null,"abstract":"Thyroid cancer (TC) is an endocrine malignancy characterized by metabolic abnormalities, with its incidence continually on the rise. Understanding the pathogenesis of this cancer would help develop better diagnostic and therapeutic methods. We aimed to integrate single-cell transcriptomics, bulk transcriptomics, and GWAS data to identify causal associations with thyroid cancer at the gene level. We intended to utilize single-cell atlases to identify malignant cells and their characteristics, and employed SMR to search for genetic loci causally associated with thyroid cancer. We validated the expression differences of the genes at the single-cell level and bulk level, as well as through immunohistochemistry experimental results. We investigated the tumor immune microenvironment of patients, attempting to find immune subgroups with differential proportions. Based on these subgroups, we conducted multi-machine learning modeling to predict the likelihood of disease and developed a corresponding interactive web application. HMGA2, SDCCAG8, DLG5, MT1E, RABL2B, RERE, and NDUFA12 all demonstrated to varying degrees their roles in promoting or inhibiting the occurrence and development of thyroid cancer, with HMGA2 showing consistency across all analyses. We also identified some immune subtypes significantly associated with TC and chose markers of T_cell_C8_STMN1 to construct patient diagnostic models. Through various combinations of machine learning feature selection and model construction, we ultimately built 178 diagnostic models, with the combination of glmBoost+RF having the best diagnostic performance (Average AUPR: 0.9915). The predictive web pages ( https://zclab-cnp.shinyapps.io/TC-WEB/ ) can provide convenience and reference for clinical personnel.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 1","pages":"116-131"},"PeriodicalIF":5.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538927","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}
Cisplatin resistance remains a significant challenge in treating lung squamous cell carcinoma (LUSC). The role of FADD in this resistance requires further investigation. Our study revealed that FADD is overexpressed in LUSC patients, correlating with lower survival rates. We also discovered that long-term cisplatin-resistant LUSC cell lines (LUSC-CR) had elevated FADD protein levels, and reducing FADD restored their cisplatin sensitivity. At the same time, LUSC-CR cells resisted cisplatin-induced DNA damage and had enhanced DNA repair, linked to P53’s negative regulation of FADD. Additionally, knockdown of the long non-coding RNA (lncRNA) PPFIA1-AS1 can potentiate drug resistance in LUSC cells by decelerating FADD protein turnover and elevating FADD protein levels. In essence, this study elucidated novel mechanisms underlying cisplatin resistance in LUSC, wherein the PPFIA1-AS1/FADD axis regulates DNA damage and repair. Consequently, targeting the PPFIA1-AS1/FADD axis may present a promising avenue for overcoming cisplatin resistance and enhancing the prognosis of LUSC patients.
{"title":"From resistance to sensitivity: the impact of FADD and lncRNA PPFIA1-AS1 on cisplatin treatment in LUSC","authors":"Xiaoyao Chang, Dangran Li, Yuanhao Tan, Fangfang Cai, Shuilian Fu, Hongqin Zhuang, Zi-Chun Hua","doi":"10.1038/s41417-025-00986-6","DOIUrl":"10.1038/s41417-025-00986-6","url":null,"abstract":"Cisplatin resistance remains a significant challenge in treating lung squamous cell carcinoma (LUSC). The role of FADD in this resistance requires further investigation. Our study revealed that FADD is overexpressed in LUSC patients, correlating with lower survival rates. We also discovered that long-term cisplatin-resistant LUSC cell lines (LUSC-CR) had elevated FADD protein levels, and reducing FADD restored their cisplatin sensitivity. At the same time, LUSC-CR cells resisted cisplatin-induced DNA damage and had enhanced DNA repair, linked to P53’s negative regulation of FADD. Additionally, knockdown of the long non-coding RNA (lncRNA) PPFIA1-AS1 can potentiate drug resistance in LUSC cells by decelerating FADD protein turnover and elevating FADD protein levels. In essence, this study elucidated novel mechanisms underlying cisplatin resistance in LUSC, wherein the PPFIA1-AS1/FADD axis regulates DNA damage and repair. Consequently, targeting the PPFIA1-AS1/FADD axis may present a promising avenue for overcoming cisplatin resistance and enhancing the prognosis of LUSC patients.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 1","pages":"102-115"},"PeriodicalIF":5.0,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523051","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}
Newcastle disease virus (NDV) is a promising oncolytic virus, yet requires further optimization. In this study, we engineered an F-gene-chimeric NDV expressing human Interleukin 2 (hIL-2) to enhance the oncolytic efficacy of the NDV Clone30 strain. This recombinant virus, designated ovNDV-28, was then produced in suspension-cultured HEK293 cells. The therapeutic potential of ovNDV-28 was evaluated across multiple cancer cell lines, as well as in the HuH-7 xenograft and B16-F0 syngeneic models. Both in vitro and in vivo results demonstrated that ovNDV-28 significantly improved tumor growth suppression compared to the wild-type NDV. Flow cytometry revealed notable increases in tumor-infiltrating CD3⁺CD4⁺ T cells, CD3⁺CD8⁺ T cells, and CD3⁻CD49b⁺ cells, along with elevated expression levels of IFN-γ, TNF-α, perforin, and Granzyme B within tumor tissue. Comprehensive toxicological assessments conducted on B16-F0 tumor-bearing mice involved intratumoral administration of ovNDV-28 at doses of 1.12 × 10⁶ or 1.46 × 10⁷ PFU/mouse every other day for 14 days. No ovNDV-28-related biochemical, hematological, or histopathological abnormalities were observed. The virus was detected in tumor tissue, mesenteric lymph nodes, abdominal adipose tissue, brain, and biceps femoris, without evidence of blood circulation or viral shedding. This study systematically demonstrates the efficacy, safety, and pharmacokinetics of ovNDV-28, supporting its potential for clinical translation.
{"title":"Development and preclinical evaluation of ovNDV-28: a chimeric Newcastle disease virus expressing human IL-2 for cancer therapy","authors":"Tianyan Liu, Zhihang Liu, Dan Yu, Shan Jiang, Chengkai Yin, Yu Zhang, Yating Zhang, Hongna Chen, Chenfeng Zhang, Xu Li, Jiarui Yang, Shishi Liu, Zhenzhong Wang, Deshan Li","doi":"10.1038/s41417-025-00981-x","DOIUrl":"10.1038/s41417-025-00981-x","url":null,"abstract":"Newcastle disease virus (NDV) is a promising oncolytic virus, yet requires further optimization. In this study, we engineered an F-gene-chimeric NDV expressing human Interleukin 2 (hIL-2) to enhance the oncolytic efficacy of the NDV Clone30 strain. This recombinant virus, designated ovNDV-28, was then produced in suspension-cultured HEK293 cells. The therapeutic potential of ovNDV-28 was evaluated across multiple cancer cell lines, as well as in the HuH-7 xenograft and B16-F0 syngeneic models. Both in vitro and in vivo results demonstrated that ovNDV-28 significantly improved tumor growth suppression compared to the wild-type NDV. Flow cytometry revealed notable increases in tumor-infiltrating CD3⁺CD4⁺ T cells, CD3⁺CD8⁺ T cells, and CD3⁻CD49b⁺ cells, along with elevated expression levels of IFN-γ, TNF-α, perforin, and Granzyme B within tumor tissue. Comprehensive toxicological assessments conducted on B16-F0 tumor-bearing mice involved intratumoral administration of ovNDV-28 at doses of 1.12 × 10⁶ or 1.46 × 10⁷ PFU/mouse every other day for 14 days. No ovNDV-28-related biochemical, hematological, or histopathological abnormalities were observed. The virus was detected in tumor tissue, mesenteric lymph nodes, abdominal adipose tissue, brain, and biceps femoris, without evidence of blood circulation or viral shedding. This study systematically demonstrates the efficacy, safety, and pharmacokinetics of ovNDV-28, supporting its potential for clinical translation.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 1","pages":"85-101"},"PeriodicalIF":5.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145437363","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}
Pub Date : 2025-10-30DOI: 10.1038/s41417-025-00984-8
Marine Colson, Arthur Aubry, Nicolas Gaide, Philippe Lluel, Eric Oswald, Laure David
Bladder cancer is the second most common malignancy of the urogenital system, with non-muscle-invasive forms being the most prevalent. While therapy with intravesical instillation of Bacillus Calmette-Guérin (BCG) is widely used, it shows variable efficacy and notable side effects, which prompts the need for new treatments. This study introduces a nanoscale biotherapy against bladder cancer using bacterial extracellular vesicles (bEVs) from Escherichia coli. In an orthotopic syngeneic rat model of bladder cancer with luciferase-tagged tumour cells, intravesical bEVs treatment significantly inhibited tumour growth compared to the gold standard therapy: BCG. Indeed, compared to BCG, bEVs treatment led to superior tumour regression, with 60% of treated animals showing complete tumour clearance versus 20% in the BCG-treated group. Moreover, we observed strong local immune activation, namely T cell infiltration and mucosal lymphoid aggregates, which negatively correlated with tumour size, suggesting that bEVs efficacy is due, at least in part, to their ability to induce a strong antitumor immune response. Notably, bEVs caused no mortality or systemic toxicity. Altogether, the present study constitutes a striking illustration of translational medicine, where the properties of a bacterial compound can be harnessed for patient benefit.
{"title":"Bacterial nanoparticles as a potent and safe alternative to BCG for bladder cancer immunotherapy","authors":"Marine Colson, Arthur Aubry, Nicolas Gaide, Philippe Lluel, Eric Oswald, Laure David","doi":"10.1038/s41417-025-00984-8","DOIUrl":"10.1038/s41417-025-00984-8","url":null,"abstract":"Bladder cancer is the second most common malignancy of the urogenital system, with non-muscle-invasive forms being the most prevalent. While therapy with intravesical instillation of Bacillus Calmette-Guérin (BCG) is widely used, it shows variable efficacy and notable side effects, which prompts the need for new treatments. This study introduces a nanoscale biotherapy against bladder cancer using bacterial extracellular vesicles (bEVs) from Escherichia coli. In an orthotopic syngeneic rat model of bladder cancer with luciferase-tagged tumour cells, intravesical bEVs treatment significantly inhibited tumour growth compared to the gold standard therapy: BCG. Indeed, compared to BCG, bEVs treatment led to superior tumour regression, with 60% of treated animals showing complete tumour clearance versus 20% in the BCG-treated group. Moreover, we observed strong local immune activation, namely T cell infiltration and mucosal lymphoid aggregates, which negatively correlated with tumour size, suggesting that bEVs efficacy is due, at least in part, to their ability to induce a strong antitumor immune response. Notably, bEVs caused no mortality or systemic toxicity. Altogether, the present study constitutes a striking illustration of translational medicine, where the properties of a bacterial compound can be harnessed for patient benefit.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 1","pages":"76-84"},"PeriodicalIF":5.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408083","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}
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