Pub Date : 2025-12-13DOI: 10.1016/j.tranon.2025.102645
Caitland A Love , John W Figg , Mia Engelbart , Illeana West , Catherine Flores
Glioblastoma (GBM) remains one of the most lethal brain malignancies, with an abysmal five-year survival rate near 6 %. Despite advances in tumor biology, clinical outcomes have not improved, partially due to glioma stem cells (GSCs) that drive treatment resistance. Radial glial cells (RGCs), recognized as key progenitors in neurodevelopment, have recently gained attention in GBM research due to RGC-like populations being identified in GBM. RGCs have striking similarities with GSCs, including their mechanisms of self-renewal, pluripotency, and migration. This review highlights those parallels between as well as recent studies on their critical intersections to expand our comprehension of neurodevelopmental paradigms in GBM. Understanding these parallels may uncover developmental pathways that can be exploited to improve therapeutic strategies for GBM.
{"title":"Radial glial cells and glioblastoma: how developmental neurobiology can inform our understanding of brain cancer initiation, treatment resistance, and resilience","authors":"Caitland A Love , John W Figg , Mia Engelbart , Illeana West , Catherine Flores","doi":"10.1016/j.tranon.2025.102645","DOIUrl":"10.1016/j.tranon.2025.102645","url":null,"abstract":"<div><div>Glioblastoma (GBM) remains one of the most lethal brain malignancies, with an abysmal five-year survival rate near 6 %. Despite advances in tumor biology, clinical outcomes have not improved, partially due to glioma stem cells (GSCs) that drive treatment resistance. Radial glial cells (RGCs), recognized as key progenitors in neurodevelopment, have recently gained attention in GBM research due to RGC-like populations being identified in GBM. RGCs have striking similarities with GSCs, including their mechanisms of self-renewal, pluripotency, and migration. This review highlights those parallels between as well as recent studies on their critical intersections to expand our comprehension of neurodevelopmental paradigms in GBM. Understanding these parallels may uncover developmental pathways that can be exploited to improve therapeutic strategies for GBM.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102645"},"PeriodicalIF":5.0,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.tranon.2025.102625
Xiaodong Shi , Baiyang Song , Boqian Wang , Anyi Chen , Jiasheng Hu , Guohai Xie , Jialing Huang , Caiyun Huang , Yue Cheng , Zejun Yan , Wei Du
Objective
TOP2A (Topoisomerase II alpha) is significantly overexpressed in kidney renal clear cell carcinoma (KIRC), and its expression level is significantly associated with accelerated tumor progression and poor prognosis in patients. Therefore, the aim of this study is to systematically analyze the biological functions of TOP2A-related molecular markers in KIRC by constructing a TOP2A based index clinical model. Additionally, we aim to screen potential therapeutic targets to guide the optimization of clinical intervention strategies.
Methods
Integrated TCGA-KIRC data were standardized and analyzed via PCA. Differentially expressed genes between TOP2A high/low expression groups were screened and functionally annotated (GO/KEGG). WGCNA identified core TOP2A-associated modules, combined with Cox regression to construct a prognostic model. GSEA evaluated pathway activity, immune infiltration, and immune checkpoint correlations. Regulatory networks (miRNA/lncRNA/RBP), mutation profiles, and methylation-transcriptome interactions were explored.
Results
5500 TOP2A-related deregulated genes were identified, with core modules enriched in cell cycle/DNA replication pathways. The TOP2A-index model inversely correlated with patient survival. High TOP2A expression scores showed positive associations with immune checkpoint genes. Multi-omics analyses revealed global regulatory networks linking TOP2A to tumor microenvironment modulation.
Conclusion
This study developed a TOP2A based index clinical model that will aid in predicting the prognosis of KIRC patients.
目的top2a （Topoisomerase II α）在肾透明细胞癌（KIRC）中显著过表达，其表达水平与患者肿瘤进展加快和预后不良显著相关。因此，本研究的目的是通过构建基于TOP2A的指数临床模型，系统分析TOP2A相关分子标志物在KIRC中的生物学功能。此外，我们旨在筛选潜在的治疗靶点，以指导临床干预策略的优化。方法对TCGA-KIRC综合数据进行标准化分析。筛选TOP2A高/低表达组间差异表达基因并进行功能注释（GO/KEGG）。WGCNA确定核心top2a相关模块，结合Cox回归构建预后模型。GSEA评估了途径活性、免疫浸润和免疫检查点相关性。研究探讨了调控网络（miRNA/lncRNA/RBP）、突变谱和甲基化-转录组相互作用。结果共鉴定出5500个top2a相关失调控基因，其核心模块富集于细胞周期/DNA复制通路。top2a指数模型与患者生存率呈负相关。高TOP2A表达评分与免疫检查点基因呈正相关。多组学分析揭示了将TOP2A与肿瘤微环境调节联系起来的全球调控网络。结论本研究建立了基于TOP2A的指数临床模型，有助于预测KIRC患者的预后。
{"title":"Development and validation of a TOP2A based index clinical model for kidney renal clear cell carcinoma","authors":"Xiaodong Shi , Baiyang Song , Boqian Wang , Anyi Chen , Jiasheng Hu , Guohai Xie , Jialing Huang , Caiyun Huang , Yue Cheng , Zejun Yan , Wei Du","doi":"10.1016/j.tranon.2025.102625","DOIUrl":"10.1016/j.tranon.2025.102625","url":null,"abstract":"<div><h3>Objective</h3><div>TOP2A (Topoisomerase II alpha) is significantly overexpressed in kidney renal clear cell carcinoma (KIRC), and its expression level is significantly associated with accelerated tumor progression and poor prognosis in patients. Therefore, the aim of this study is to systematically analyze the biological functions of TOP2A-related molecular markers in KIRC by constructing a TOP2A based index clinical model. Additionally, we aim to screen potential therapeutic targets to guide the optimization of clinical intervention strategies.</div></div><div><h3>Methods</h3><div>Integrated TCGA-KIRC data were standardized and analyzed via PCA. Differentially expressed genes between TOP2A high/low expression groups were screened and functionally annotated (GO/KEGG). WGCNA identified core TOP2A-associated modules, combined with Cox regression to construct a prognostic model. GSEA evaluated pathway activity, immune infiltration, and immune checkpoint correlations. Regulatory networks (miRNA/lncRNA/RBP), mutation profiles, and methylation-transcriptome interactions were explored.</div></div><div><h3>Results</h3><div>5500 TOP2A-related deregulated genes were identified, with core modules enriched in cell cycle/DNA replication pathways. The TOP2A-index model inversely correlated with patient survival. High TOP2A expression scores showed positive associations with immune checkpoint genes. Multi-omics analyses revealed global regulatory networks linking TOP2A to tumor microenvironment modulation.</div></div><div><h3>Conclusion</h3><div>This study developed a TOP2A based index clinical model that will aid in predicting the prognosis of KIRC patients.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102625"},"PeriodicalIF":5.0,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1016/j.tranon.2025.102540
Ting Guo , Dengyun Nie , Jie Xu , Ruifang Zhou , Yunyao Ye , Yinxing Zhu , Mei Lin
This study elucidates the biological function of GADAT2B and its underlying mechanism in ovarian cancer.The results of our experiment showed that GATAD2B highly expressed in OC tissues, which was associated with a poor prognosis. METTL3 regulated the expression of GATAD2B in OC cells via m6A methylation. And it was unveiled that up-regulation of GATAD2B significantly promoted OC growth, invasion, migration of and suppressed the tumor cell apoptosis. After transfected with sh-GATAD2B, the OC cells were just the reverse in behavior. Additionally, GATAD2B played a crucial role in regulating CD47 expression via the MYC-mediated pathway, and the further experiments showed that GATAD2B and MYC were co-localized on tumor cell membrane. The in vivo and in vitro experiments showed an important role of GATAD2B in OC growth and metastasis, as confirmed by the inhibited tumor growth and the enhanced M1 macrophage infiltration.GATAD2B m6A methylation mediated by METTL3 can promote malignant progress. And GATAD2B can promote immune escape by MYC/CD47 pathway in OC, providing a promising anti-OC therapeutic target.
{"title":"GATAD2B promotes ovarian cancer malignant progression via MYC/CD47 Axis","authors":"Ting Guo , Dengyun Nie , Jie Xu , Ruifang Zhou , Yunyao Ye , Yinxing Zhu , Mei Lin","doi":"10.1016/j.tranon.2025.102540","DOIUrl":"10.1016/j.tranon.2025.102540","url":null,"abstract":"<div><div>This study elucidates the biological function of GADAT2B and its underlying mechanism in ovarian cancer.The results of our experiment showed that GATAD2B highly expressed in OC tissues, which was associated with a poor prognosis. METTL3 regulated the expression of GATAD2B in OC cells via m6A methylation. And it was unveiled that up-regulation of GATAD2B significantly promoted OC growth, invasion, migration of and suppressed the tumor cell apoptosis. After transfected with sh-GATAD2B, the OC cells were just the reverse in behavior. Additionally, GATAD2B played a crucial role in regulating CD47 expression via the MYC-mediated pathway, and the further experiments showed that GATAD2B and MYC were co-localized on tumor cell membrane. The in vivo and in vitro experiments showed an important role of GATAD2B in OC growth and metastasis, as confirmed by the inhibited tumor growth and the enhanced M1 macrophage infiltration.GATAD2B m6A methylation mediated by METTL3 can promote malignant progress. And GATAD2B can promote immune escape by MYC/CD47 pathway in OC, providing a promising anti-OC therapeutic target.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102540"},"PeriodicalIF":5.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1016/j.tranon.2025.102636
Shatovisha Dey , Deep Pandya , Tammy Lo , Ryan Narbutas , Bhavna Khandpur , Pramila Krumholtz , Mohammadreza Shervinrad , Kiyoe Sullivan , Deborah August , Sarah Evans , Saraswathi Nair , Nader Okby , Gregory Niland , Richard C Frank
Background
The average survival of advanced pancreatic cancer (APC) is 6–12 months with first-line chemotherapy. Only one-third receive second-line treatment. No early biomarker exists to guide chemotherapy efficacy before tumor progression occurs. Circulating small extracellular vesicles (sEVs) are a potential source of biomarker discovery.
Methods
Longitudinally collected sEVs from chemotherapy treated APC patients at pre-treatment, remission and relapse underwent proteomic profiling by mass spectrometry (MS). GO and KEGG analyses assessed differential protein characteristics, while protein-protein interactions and upstream analyses explored potential mechanisms. A candidate biomarker was validated by ELISA in larger patient cohorts of responders and non-responders. Gene knock-down and overexpression studies and tumor immunohistochemistry (IHC) evaluated potential function and localization.
Results
MS identified 34 proteins unique to remission, 132 unique to treatment resistance, and 9 differential across both phases. Complement cascade alterations best reflected response to treatment. Lectin pathway component MASP2 (Mannose-Binding Lectin-Associated Serine Protease 2) emerged as a predictive biomarker: >20 % decline in sEV-MASP2 levels at month 2 (M2) of chemotherapy predicted response in 72 % of responders, whereas >20 % increase predicted treatment resistance in 73 % of non-responders. sEV-MASP2 at M2 was prognostic for survival (11 vs. 8 months; p = 0.0037), unlike CA 19–9 (11 vs. 12 months) and retained significance when CA 19–9 was unevaluable. Functional data indicated that sEV-MASP2 alterations largely reflect systemic rather than tumor site-specific activity.
Conclusions
Complement pathway activity tracks with chemotherapy response and resistance in PC. Changes in sEV-MASP2 may serve as an early predictive/prognostic biomarker, helping to improve decision making in this lethal malignancy.
{"title":"Serial proteomic analysis identifies small extracellular vesicle-MASP2 as an early biomarker of chemotherapy response in advanced pancreatic cancer","authors":"Shatovisha Dey , Deep Pandya , Tammy Lo , Ryan Narbutas , Bhavna Khandpur , Pramila Krumholtz , Mohammadreza Shervinrad , Kiyoe Sullivan , Deborah August , Sarah Evans , Saraswathi Nair , Nader Okby , Gregory Niland , Richard C Frank","doi":"10.1016/j.tranon.2025.102636","DOIUrl":"10.1016/j.tranon.2025.102636","url":null,"abstract":"<div><h3>Background</h3><div>The average survival of advanced pancreatic cancer (APC) is 6–12 months with first-line chemotherapy. Only one-third receive second-line treatment. No early biomarker exists to guide chemotherapy efficacy before tumor progression occurs. Circulating small extracellular vesicles (sEVs) are a potential source of biomarker discovery.</div></div><div><h3>Methods</h3><div>Longitudinally collected sEVs from chemotherapy treated APC patients at pre-treatment, remission and relapse underwent proteomic profiling by mass spectrometry (MS). GO and KEGG analyses assessed differential protein characteristics, while protein-protein interactions and upstream analyses explored potential mechanisms. A candidate biomarker was validated by ELISA in larger patient cohorts of responders and non-responders. Gene knock-down and overexpression studies and tumor immunohistochemistry (IHC) evaluated potential function and localization.</div></div><div><h3>Results</h3><div>MS identified 34 proteins unique to remission, 132 unique to treatment resistance, and 9 differential across both phases. Complement cascade alterations best reflected response to treatment. Lectin pathway component MASP2 (Mannose-Binding Lectin-Associated Serine Protease 2) emerged as a predictive biomarker: >20 % decline in sEV-MASP2 levels at month 2 (M2) of chemotherapy predicted response in 72 % of responders, whereas >20 % increase predicted treatment resistance in 73 % of non-responders. sEV-MASP2 at M2 was prognostic for survival (11 vs. 8 months; <em>p</em> = 0.0037), unlike CA 19–9 (11 vs. 12 months) and retained significance when CA 19–9 was unevaluable. Functional data indicated that sEV-MASP2 alterations largely reflect systemic rather than tumor site-specific activity.</div></div><div><h3>Conclusions</h3><div>Complement pathway activity tracks with chemotherapy response and resistance in PC. Changes in sEV-MASP2 may serve as an early predictive/prognostic biomarker, helping to improve decision making in this lethal malignancy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102636"},"PeriodicalIF":5.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1016/j.tranon.2025.102638
San Ha Han , Hyosun Seo , Ji Yoon Lee , Yoo Jin Cheon , Sein Han , Mun Ju Choi , Hyun Min Lee , Dae Shick Kim , Dongho Choi , Chun Jeih Ryu
B7-H3 is highly expressed with limited heterogeneity in various cancer types including hepatocellular carcinoma (HCC) but shows low expression in normal tissues. We generated monoclonal antibodies (MAbs) against surface molecules on human embryonic stem cells (hESCs) and found that NPB40, one of the MAbs, binds to HCC cells, but only weakly to primary hepatocytes. Immunoprecipitation with mass spectrometry identified that NPB40 recognizes B7-H3. In tumorsphere cultures, the expression of B7-H3 interacting with NPB40 was significantly increased, as were known cancer stem cell (CSC) markers. After cell sorting by NPB40, NPB40-high HCC cells showed higher clonogenic survival than NPB40-low HCC cells, suggesting B7-H3 as a potential CSC marker on HCC cells. NPB40 and Chi-NPB40, a chimeric form of NPB40, induced internalization of B7-H3 and inhibited cell proliferation of HCC cells by toxic payload delivery via anti-human secondary antibody drug conjugates (ADCs) and Chi-NPB40 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells in vitro. NPB40 and Chi-NPB40 injection also suppressed tumor growth in a xenograft nude mouse model of HCC. The results suggest that NPB40 may be developed as a therapeutic antibody for HCC patients.
{"title":"A monoclonal antibody targeting B7-H3 in human embryonic stem cells exhibits anti-tumor activity in hepatocellular carcinoma xenografts","authors":"San Ha Han , Hyosun Seo , Ji Yoon Lee , Yoo Jin Cheon , Sein Han , Mun Ju Choi , Hyun Min Lee , Dae Shick Kim , Dongho Choi , Chun Jeih Ryu","doi":"10.1016/j.tranon.2025.102638","DOIUrl":"10.1016/j.tranon.2025.102638","url":null,"abstract":"<div><div>B7-H3 is highly expressed with limited heterogeneity in various cancer types including hepatocellular carcinoma (HCC) but shows low expression in normal tissues. We generated monoclonal antibodies (MAbs) against surface molecules on human embryonic stem cells (hESCs) and found that NPB40, one of the MAbs, binds to HCC cells, but only weakly to primary hepatocytes. Immunoprecipitation with mass spectrometry identified that NPB40 recognizes B7-H3. In tumorsphere cultures, the expression of B7-H3 interacting with NPB40 was significantly increased, as were known cancer stem cell (CSC) markers. After cell sorting by NPB40, NPB40-high HCC cells showed higher clonogenic survival than NPB40-low HCC cells, suggesting B7-H3 as a potential CSC marker on HCC cells. NPB40 and Chi-NPB40, a chimeric form of NPB40, induced internalization of B7-H3 and inhibited cell proliferation of HCC cells by toxic payload delivery via anti-human secondary antibody drug conjugates (ADCs) and Chi-NPB40 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells <em>in vitro</em>. NPB40 and Chi-NPB40 injection also suppressed tumor growth in a xenograft nude mouse model of HCC. The results suggest that NPB40 may be developed as a therapeutic antibody for HCC patients.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102638"},"PeriodicalIF":5.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1016/j.tranon.2025.102627
Zhenhao Huang , Jing Luo , Jintong He , Qihui Hu , Rui Liao , Jie Xu , Peng Guo , Zhipeng Liu , Nan You , Baoyong Zhou , Rui Tao
Background
Gallbladder cancer (GBC) has poor prognosis, and reliable preoperative biomarkers remain limited. Systemic inflammation-based indices, including systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR), may predict outcomes, but their comparative value and association with TNM stage are unclear.
Methods
This multicenter retrospective study included 210 patients who underwent curative-intent resection for GBC (2015–2023). Preoperative SII, NLR, and MLR were calculated from peripheral blood counts. Prognostic performance was evaluated by time-dependent ROC, Kaplan–Meier, and Cox regression analyses. Restricted cubic spline models assessed non-linear associations. Associations with TNM stage were analyzed using the Jonckheere–Terpstra trend test, and stratified survival analysis was conducted.
Results
SII showed the highest predictive accuracy for overall survival (OS, AUC = 0.745) and recurrence-free survival (RFS, AUC = 0.689), outperforming NLR and MLR. In multivariable analysis, only elevated SII independently predicted poorer OS (HR = 4.601, 95% CI: 1.178–17.965, P = 0.028). Restricted cubic spline revealed an “S-shaped” non-linear relationship between SII and OS risk and a linear association with RFS. SII levels significantly increased with advancing TNM stage (P = 0.042) and provided superior prognostic stratification in advanced disease, while NLR and MLR showed weaker stage-related trends.
Conclusions
Among SII, NLR, and MLR, preoperative SII showed comparatively stronger and more consistent associations within this retrospective multicenter cohort. SII independently predicted OS, correlated with TNM stage, and appeared to offer better stratification in advanced disease. As a simple and readily available biomarker, SII may be considered to complement TNM staging for preoperative risk assessment; however, these findings should be interpreted cautiously and require confirmation in prospective multicenter studies.
{"title":"Comparative prognostic value of preoperative SII, NLR, and MLR and their association with TNM staging in gallbladder cancer: A multicenter retrospective study","authors":"Zhenhao Huang , Jing Luo , Jintong He , Qihui Hu , Rui Liao , Jie Xu , Peng Guo , Zhipeng Liu , Nan You , Baoyong Zhou , Rui Tao","doi":"10.1016/j.tranon.2025.102627","DOIUrl":"10.1016/j.tranon.2025.102627","url":null,"abstract":"<div><h3>Background</h3><div>Gallbladder cancer (GBC) has poor prognosis, and reliable preoperative biomarkers remain limited. Systemic inflammation-based indices, including systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR), may predict outcomes, but their comparative value and association with TNM stage are unclear.</div></div><div><h3>Methods</h3><div>This multicenter retrospective study included 210 patients who underwent curative-intent resection for GBC (2015–2023). Preoperative SII, NLR, and MLR were calculated from peripheral blood counts. Prognostic performance was evaluated by time-dependent ROC, Kaplan–Meier, and Cox regression analyses. Restricted cubic spline models assessed non-linear associations. Associations with TNM stage were analyzed using the Jonckheere–Terpstra trend test, and stratified survival analysis was conducted.</div></div><div><h3>Results</h3><div>SII showed the highest predictive accuracy for overall survival (OS, AUC = 0.745) and recurrence-free survival (RFS, AUC = 0.689), outperforming NLR and MLR. In multivariable analysis, only elevated SII independently predicted poorer OS (HR = 4.601, 95% CI: 1.178–17.965, <em>P</em> = 0.028). Restricted cubic spline revealed an “S-shaped” non-linear relationship between SII and OS risk and a linear association with RFS. SII levels significantly increased with advancing TNM stage (<em>P</em> = 0.042) and provided superior prognostic stratification in advanced disease, while NLR and MLR showed weaker stage-related trends.</div></div><div><h3>Conclusions</h3><div>Among SII, NLR, and MLR, preoperative SII showed comparatively stronger and more consistent associations within this retrospective multicenter cohort. SII independently predicted OS, correlated with TNM stage, and appeared to offer better stratification in advanced disease. As a simple and readily available biomarker, SII may be considered to complement TNM staging for preoperative risk assessment; however, these findings should be interpreted cautiously and require confirmation in prospective multicenter studies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"64 ","pages":"Article 102627"},"PeriodicalIF":5.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal forms of cancer, with a dismal survival rate. Therapeutic options are restricted in surgery for patients with resectable disease and in chemotherapy for those with unresectable disease. The potential benefits of radiotherapy (RT) or chemoradiotherapy (CRT) have been extensively investigated in both neoadjuvant and adjuvant settings in the management of patients with PDAC. Nevertheless, a substantial number of clinical trials have yielded conflicting findings, thereby rendering the impact of RT on patient survival and margin-negative (R0) resection inconclusive. A comprehensive examination of the historical evolution of RT in PDAC, encompassing the identification of both constraints and opportunities for advancement, is essential to establish RT as a promising therapeutic avenue for patients with PDAC. The aim of this review is to provide a synthesis of past clinical trials and future studies to elucidate the evolving role of RT in the management of PDAC as adjuvant and neoadjuvant CRT across different stages of the disease.
{"title":"Radiotherapy in the management of PDAC, from past to present","authors":"Julie Dardare , Nicolas Martz , Andréa Witz , Margaux Betz , Cassandra Michel , Pauline Gilson , Jean-Louis Merlin , Aurélien Lambert , Alexandre Harle","doi":"10.1016/j.tranon.2025.102632","DOIUrl":"10.1016/j.tranon.2025.102632","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal forms of cancer, with a dismal survival rate. Therapeutic options are restricted in surgery for patients with resectable disease and in chemotherapy for those with unresectable disease. The potential benefits of radiotherapy (RT) or chemoradiotherapy (CRT) have been extensively investigated in both neoadjuvant and adjuvant settings in the management of patients with PDAC. Nevertheless, a substantial number of clinical trials have yielded conflicting findings, thereby rendering the impact of RT on patient survival and margin-negative (R0) resection inconclusive. A comprehensive examination of the historical evolution of RT in PDAC, encompassing the identification of both constraints and opportunities for advancement, is essential to establish RT as a promising therapeutic avenue for patients with PDAC. The aim of this review is to provide a synthesis of past clinical trials and future studies to elucidate the evolving role of RT in the management of PDAC as adjuvant and neoadjuvant CRT across different stages of the disease.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102632"},"PeriodicalIF":5.0,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-07DOI: 10.1016/j.tranon.2025.102633
Maria Edwards , Pablo Caruana , Mireia Escar , Maria Virtudes Céspedes
Despite therapeutic advancements, ovarian cancer remains one of the most lethal gynaecological malignancies, highlighting the urgent need for innovative drug discovery approaches. Traditional 2D cell line models fail to accurately replicate the complexity of the tumour and its microenvironment (TME), leading to suboptimal drug evaluations. Organotypic tumour slice culture (OTSC) has emerged as a promising 3D ex vivo platform that preserves native tissue architecture, cellular interactions, and molecular heterogeneity of the tumour and its TME, providing a more physiologically relevant system for drug testing. This review examines the evolution of OTSC in ovarian cancer and its applications across chemotherapy, targeted therapy, immunotherapy, and virotherapy. We highlight the role of OTSC in identifying predictive biomarkers of drug response, drug resistance mechanisms – including those in the stroma – and elucidating novel therapeutic strategies. While OTSC has demonstrated its ability to rapidly provide insights into patient-specific responses, further integration of advanced multi-omics analyses could enhance its potential as a precision medicine platform. With its 3D heterogenic complexity, OTSC could also facilitate the development and evaluation of TME-directed therapies, novel multitarget drugs, and tumour-targeting drug delivery systems, ultimately shaping the future of ovarian cancer therapy and improving clinical outcomes.
{"title":"Shaping the future one slice at a time: How 3D organotypic tumour slice models are driving drug discovery in ovarian cancer","authors":"Maria Edwards , Pablo Caruana , Mireia Escar , Maria Virtudes Céspedes","doi":"10.1016/j.tranon.2025.102633","DOIUrl":"10.1016/j.tranon.2025.102633","url":null,"abstract":"<div><div>Despite therapeutic advancements, ovarian cancer remains one of the most lethal gynaecological malignancies, highlighting the urgent need for innovative drug discovery approaches. Traditional 2D cell line models fail to accurately replicate the complexity of the tumour and its microenvironment (TME), leading to suboptimal drug evaluations. Organotypic tumour slice culture (OTSC) has emerged as a promising 3D <em>ex vivo</em> platform that preserves native tissue architecture, cellular interactions, and molecular heterogeneity of the tumour and its TME, providing a more physiologically relevant system for drug testing. This review examines the evolution of OTSC in ovarian cancer and its applications across chemotherapy, targeted therapy, immunotherapy, and virotherapy. We highlight the role of OTSC in identifying predictive biomarkers of drug response, drug resistance mechanisms – including those in the stroma – and elucidating novel therapeutic strategies. While OTSC has demonstrated its ability to rapidly provide insights into patient-specific responses, further integration of advanced multi-omics analyses could enhance its potential as a precision medicine platform. With its 3D heterogenic complexity, OTSC could also facilitate the development and evaluation of TME-directed therapies, novel multitarget drugs, and tumour-targeting drug delivery systems, ultimately shaping the future of ovarian cancer therapy and improving clinical outcomes.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102633"},"PeriodicalIF":5.0,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although several new therapies against acute myeloid leukaemia (AML) have emerged the past years, patients who are ineligible for intensive chemotherapy are still treated with less effective treatments to minimise therapy-associated mortality. Several phenazine 5,10-dioxide derivates have previously demonstrated to selectively induce apoptosis in human AML cells. In the present work, we have continued investigations on phenazine 5,10-dioxides to reveal their therapeutic potential in AML using in vitro and in vivo experiments. From a panel of primary AML blasts from 61 non-selected patients, 58 showed high or intermediate response to treatment with the phenazine 5,10-dioxides. This included blasts with biological characteristics associated with poor prognosis, such as FLT3 internal tandem duplication, NPM-1 wild type, CD34+, and adverse cytogenetics. The phenazine 5,10-dioxides cytotoxicity towards primary blasts correlated with the blast’s sensitivity to daunorubicin, presumably due to similar mode of action towards AML cells. Three phenazine 5,10-dioxides had low toxicity in zebrafish larvae, and from these, two were found effective towards zebrafish larvae AML xenografts. Additionally, synergism with the AML drug venetoclax (VTX) was found in the AML cell lines MOLM-13 and MV4–11. The efficacy of phenazine 5,10-dioxides towards primary AML blasts, synergism with VTX and low toxicity in effective concentrations in zebrafish larva AML xenografts suggests potential for these compounds in future AML therapy for patients unfit for intensive chemotherapy.
{"title":"Phenazine 5,10-dioxide analogues as potential therapeutics in AML: Efficacy on patient-derived blasts, in zebrafish larvae xenografts and synergy with venetoclax","authors":"Ingeborg Nerbø Reiten , Reidun Aesoy , Jan-Lukas Førde , Goraksha Machhindra Khose , Elvar Örn Viktorsson , Øystein Bruserud , Pål Rongved , Håkon Reikvam , Lars Herfindal","doi":"10.1016/j.tranon.2025.102628","DOIUrl":"10.1016/j.tranon.2025.102628","url":null,"abstract":"<div><div>Although several new therapies against acute myeloid leukaemia (AML) have emerged the past years, patients who are ineligible for intensive chemotherapy are still treated with less effective treatments to minimise therapy-associated mortality. Several phenazine 5,10-dioxide derivates have previously demonstrated to selectively induce apoptosis in human AML cells. In the present work, we have continued investigations on phenazine 5,10-dioxides to reveal their therapeutic potential in AML using in vitro and in vivo experiments. From a panel of primary AML blasts from 61 non-selected patients, 58 showed high or intermediate response to treatment with the phenazine 5,10-dioxides. This included blasts with biological characteristics associated with poor prognosis, such as <em>FLT3</em> internal tandem duplication, <em>NPM-1</em> wild type, CD34<sup>+</sup>, and adverse cytogenetics. The phenazine 5,10-dioxides cytotoxicity towards primary blasts correlated with the blast’s sensitivity to daunorubicin, presumably due to similar mode of action towards AML cells. Three phenazine 5,10-dioxides had low toxicity in zebrafish larvae, and from these, two were found effective towards zebrafish larvae AML xenografts. Additionally, synergism with the AML drug venetoclax (VTX) was found in the AML cell lines MOLM-13 and MV4–11. The efficacy of phenazine 5,10-dioxides towards primary AML blasts, synergism with VTX and low toxicity in effective concentrations in zebrafish larva AML xenografts suggests potential for these compounds in future AML therapy for patients unfit for intensive chemotherapy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102628"},"PeriodicalIF":5.0,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-06DOI: 10.1016/j.tranon.2025.102631
Bo Lv , Lan Li , Man Liu , Su-zhao Zou
Circular RNAs (circRNAs), a class of covalently closed noncoding RNAs with remarkable stability and cell-type specificity, have emerged as critical regulators of cancer immunology. Increasing evidence reveals that circRNAs orchestrate tumor immune escape through multilayered mechanisms spanning post-transcriptional, post-translational, and metabolic levels, thereby reshaping the tumor immune microenvironment (TIME). A central theme involves the maintenance of PD-L1 homeostasis: circRNAs modulate PD-L1 stability via m^6A/IGF2BP-dependent RNA–protein interactions, protect PD-L1 from ubiquitin-mediated degradation through deubiquitinases, or promote its phosphorylation to prevent proteasomal turnover. Beyond tumor-intrinsic regulation, circRNAs are packaged into exosomes or small extracellular vesicles and delivered to immune cells, where they induce CD8^+ T-cell dysfunction, foster regulatory T-cell expansion, or reprogram myeloid-derived suppressor cells and macrophages toward immunosuppressive phenotypes. These intercellular communications contribute to resistance against immune checkpoint inhibitors and conventional therapies. In parallel, circRNAs are increasingly recognized as both therapeutic targets and agents. Strategies that silence oncogenic circRNAs using nanoparticles restore drug sensitivity and reinvigorate antitumor immunity, while synthetic or in vitro–transcribed circRNAs encoding immunostimulatory factors such as IL-12 demonstrate potent capacity to remodel TIME. The integration of tumor-tailored lipid nanoparticles, biomimetic vesicles, and rational circRNA design underscores a new wave of precision immunotherapy. This review highlights the mechanistic diversity of circRNAs in immune evasion, their roles in therapeutic resistance, and the translational opportunities offered by nanomedicine-based delivery systems. By bridging basic immunology and therapeutic innovation, circRNAs hold promise as next-generation targets and tools in cancer immunotherapy.
{"title":"Circular RNAs in cancer immunology: Immune escape, therapeutic resistance, and nanomedicine synergies","authors":"Bo Lv , Lan Li , Man Liu , Su-zhao Zou","doi":"10.1016/j.tranon.2025.102631","DOIUrl":"10.1016/j.tranon.2025.102631","url":null,"abstract":"<div><div>Circular RNAs (circRNAs), a class of covalently closed noncoding RNAs with remarkable stability and cell-type specificity, have emerged as critical regulators of cancer immunology. Increasing evidence reveals that circRNAs orchestrate tumor immune escape through multilayered mechanisms spanning post-transcriptional, post-translational, and metabolic levels, thereby reshaping the tumor immune microenvironment (TIME). A central theme involves the maintenance of PD-L1 homeostasis: circRNAs modulate PD-L1 stability via m^6A/IGF2BP-dependent RNA–protein interactions, protect PD-L1 from ubiquitin-mediated degradation through deubiquitinases, or promote its phosphorylation to prevent proteasomal turnover. Beyond tumor-intrinsic regulation, circRNAs are packaged into exosomes or small extracellular vesicles and delivered to immune cells, where they induce CD8^+ <em>T</em>-cell dysfunction, foster regulatory T-cell expansion, or reprogram myeloid-derived suppressor cells and macrophages toward immunosuppressive phenotypes. These intercellular communications contribute to resistance against immune checkpoint inhibitors and conventional therapies. In parallel, circRNAs are increasingly recognized as both therapeutic targets and agents. Strategies that silence oncogenic circRNAs using nanoparticles restore drug sensitivity and reinvigorate antitumor immunity, while synthetic or in vitro–transcribed circRNAs encoding immunostimulatory factors such as IL-12 demonstrate potent capacity to remodel TIME. The integration of tumor-tailored lipid nanoparticles, biomimetic vesicles, and rational circRNA design underscores a new wave of precision immunotherapy. This review highlights the mechanistic diversity of circRNAs in immune evasion, their roles in therapeutic resistance, and the translational opportunities offered by nanomedicine-based delivery systems. By bridging basic immunology and therapeutic innovation, circRNAs hold promise as next-generation targets and tools in cancer immunotherapy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102631"},"PeriodicalIF":5.0,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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