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}
This study aims to develop and validate a CT-based radiomics model for predicting the prognosis of head and neck cancer patients, particularly those with nasopharyngeal carcinoma (NPC), following intensity-modulated radiation therapy (IMRT).
Methods
We conducted a retrospective analysis involving 392 pathologically confirmed NPC patients from two centers. Center A contributed 226 patients to the training cohort, while Center B provided 64 patients for the validation cohort. Features extracted from CT images were utilized to develop two predictive models: a clinically combined radiomics model and a standalone radiomics model. Dimensionality reduction and nested cross-validation were employed in the model development process. The performance of the models was assessed and validated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA), with differences between the models evaluated using the DeLong test.
Results
Our findings indicate that the clinically combined radiomics model outperforms the standalone radiomics model in prognostic prediction. The area under the curve (AUC) for the combined model was 0.90 in the training cohort, while the validation cohort achieved an AUC of 0.86. DCA further confirmed that the performance of all models exceeded that of blindly predicting patient outcomes as either all negative or all positive. Subsequent comparisons using the DeLong test revealed significant differences in predictive performance between the standalone radiomics model and the clinically combined radiomics model, with P-values <0.05.
Conclusion
The clinically combined radiomics model demonstrates promising performance in predicting the prognosis of NPC patients following IMRT.
{"title":"Prediction of local recurrence in cohorts of head and neck cancer patients after intensity-modulated radiation therapy based on CT radiomics: A double-center observation study","authors":"Jing Xu, Qing Liu, Yue Yin, Junhang Gao, Guanglu Dong","doi":"10.1016/j.tranon.2025.102622","DOIUrl":"10.1016/j.tranon.2025.102622","url":null,"abstract":"<div><h3>Objective</h3><div>This study aims to develop and validate a CT-based radiomics model for predicting the prognosis of head and neck cancer patients, particularly those with nasopharyngeal carcinoma (NPC), following intensity-modulated radiation therapy (IMRT).</div></div><div><h3>Methods</h3><div>We conducted a retrospective analysis involving 392 pathologically confirmed NPC patients from two centers. Center A contributed 226 patients to the training cohort, while Center B provided 64 patients for the validation cohort. Features extracted from CT images were utilized to develop two predictive models: a clinically combined radiomics model and a standalone radiomics model. Dimensionality reduction and nested cross-validation were employed in the model development process. The performance of the models was assessed and validated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA), with differences between the models evaluated using the DeLong test.</div></div><div><h3>Results</h3><div>Our findings indicate that the clinically combined radiomics model outperforms the standalone radiomics model in prognostic prediction. The area under the curve (AUC) for the combined model was 0.90 in the training cohort, while the validation cohort achieved an AUC of 0.86. DCA further confirmed that the performance of all models exceeded that of blindly predicting patient outcomes as either all negative or all positive. Subsequent comparisons using the DeLong test revealed significant differences in predictive performance between the standalone radiomics model and the clinically combined radiomics model, with P-values <0.05.</div></div><div><h3>Conclusion</h3><div>The clinically combined radiomics model demonstrates promising performance in predicting the prognosis of NPC patients following IMRT.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102622"},"PeriodicalIF":5.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669760","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 : 2025-12-03DOI: 10.1016/j.tranon.2025.102615
Anas Gazzah , Nils Ternès , Joon Sang Lee , Emma Wang , Dimitri Carene , Hong Wang , Nina Masson , Eric Boitier , Aude Lartigau , Nathalie Mace , Mustapha Chadjaa , Colette Dib , Manoel Nunes , Gaëlle Muzard , Sandrine Longuemaux-Valence , Anne-Laure Bauchet
Background
Tusamitamab ravtansine demonstrated antitumor activity in the Phase 1/1b study of advanced non-squamous non-small cell lung cancer with high (HE, ≥2+ intensity in ≥50 % of tumor cells) or moderate (ME, ≥2+ intensity in ≥1 % to <50 % of tumor cells) carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression. Tumor CEACAM5 expression, biomarker associations and whether biomarkers predict objective response rate (ORR) were explored.
Methods
We assessed CEACAM5, circulating CEACAM5 (cCEACAM5) and CEA (cCEA). Enrollment was according to immunohistochemistry (IHC) CEACAM5 membrane expression: HE (n=64) and ME (n=28). Patients received tusamitamab ravtansine 100 mg/m2 intravenously every 2 weeks.
Results
cCEA and cCEACAM5 were strongly associated (Spearman ρ, 0.99), with moderate associations between IHC CEACAM5 and cCEA or cCEACAM5 (Spearman ρ, 0.43 and 0.38). In patients with baseline cCEA data, 40.3 % (25/62) of HE and 25 % (7/28) of ME had cCEA ≥100 µg/L (median: 71.6 µg/L [1–8809] versus 12.4 µg/L [0.5–684]). Among response-evaluable patients in HE, ORR for high cCEA (≥100 µg/L) was 41.7 % (10/24) versus 8.1 % (3/37) for low cCEA, and in ME, ORR was 0/7 versus 10 % (2/20). Elevated CEACAM5 mRNA was observed in HE versus ME (P = 0.0027). EGFR and KRAS alterations were present in 44.8 % and 65.5 % of HE and in 21.4 % and 78.6 % of ME patients, respectively.
Conclusions
In CEACAM5 HE, the ORR was greater with high versus low cCEA. Associations were observed between cCEA and cCEACAM5; IHC CEACAM5, cCEA, and cCEACAM5; IHC CEACAM5 and CEACAM5 mRNA, but not between IHC CEACAM5 and oncogenic drivers.
{"title":"Biomarker analysis from a Phase 1/1b study of tusamitamab ravtansine in patients with advanced non-small cell lung cancer","authors":"Anas Gazzah , Nils Ternès , Joon Sang Lee , Emma Wang , Dimitri Carene , Hong Wang , Nina Masson , Eric Boitier , Aude Lartigau , Nathalie Mace , Mustapha Chadjaa , Colette Dib , Manoel Nunes , Gaëlle Muzard , Sandrine Longuemaux-Valence , Anne-Laure Bauchet","doi":"10.1016/j.tranon.2025.102615","DOIUrl":"10.1016/j.tranon.2025.102615","url":null,"abstract":"<div><h3>Background</h3><div>Tusamitamab ravtansine demonstrated antitumor activity in the Phase 1/1b study of advanced non-squamous non-small cell lung cancer with high (HE, ≥2+ intensity in ≥50 % of tumor cells) or moderate (ME, ≥2+ intensity in ≥1 % to <50 % of tumor cells) carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression. Tumor CEACAM5 expression, biomarker associations and whether biomarkers predict objective response rate (ORR) were explored.</div></div><div><h3>Methods</h3><div>We assessed CEACAM5, circulating CEACAM5 (cCEACAM5) and CEA (cCEA). Enrollment was according to immunohistochemistry (IHC) CEACAM5 membrane expression: HE (<em>n</em>=64) and ME (<em>n</em>=28). Patients received tusamitamab ravtansine 100 mg/m<sup>2</sup> intravenously every 2 weeks.</div></div><div><h3>Results</h3><div>cCEA and cCEACAM5 were strongly associated (Spearman ρ, 0.99), with moderate associations between IHC CEACAM5 and cCEA or cCEACAM5 (Spearman ρ, 0.43 and 0.38). In patients with baseline cCEA data, 40.3 % (25/62) of HE and 25 % (7/28) of ME had cCEA ≥100 µg/L (median: 71.6 µg/L [1–8809] versus 12.4 µg/L [0.5–684]). Among response-evaluable patients in HE, ORR for high cCEA (≥100 µg/L) was 41.7 % (10/24) versus 8.1 % (3/37) for low cCEA, and in ME, ORR was 0/7 versus 10 % (2/20). Elevated CEACAM5 mRNA was observed in HE versus ME (<em>P</em> = 0.0027). <em>EGFR</em> and <em>KRAS</em> alterations were present in 44.8 % and 65.5 % of HE and in 21.4 % and 78.6 % of ME patients, respectively.</div></div><div><h3>Conclusions</h3><div>In CEACAM5 HE, the ORR was greater with high versus low cCEA. Associations were observed between cCEA and cCEACAM5; IHC CEACAM5, cCEA, and cCEACAM5; IHC CEACAM5 and CEACAM5 mRNA, but not between IHC CEACAM5 and oncogenic drivers.</div><div><strong>Clinical Trial Registration:</strong> NCT02187848</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102615"},"PeriodicalIF":5.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669782","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 : 2025-12-03DOI: 10.1016/j.tranon.2025.102623
Chenxuan Zhang , Peng Wang , Jia Yu , Jianhui Yuan , Lilong Zhang , Man Li
The preference of cancer cells to generate energy from glycolysis for rapid cell proliferation is called the Warburg effect. Poly(ADP-ribose) polymerase 1 (PARP1) performs various cellular functions, including poly-ADP-ribosylation and DNA repair. In the present study, we investigated the novel effects and mechanisms of PARP1 inhibition on glucose metabolism in colorectal cancer cells under hypoxia. We subjected Caco-2 and LoVo cancer cell lines to a concentration gradient of PARP1 inhibitor in a hypoxic environment induced with a tri-gas incubator (5 % CO2, 1 % O2, 94 % N2). Inhibiting PARP1 activation attenuated Poly-ADP-ribosylation, increasing the NAD+/NADH ratio. High concentrations of PARP1 significantly reduced the glucose consumption rate of the treated cells, while PARP1 inhibition depressed cell progression in a concentration-dependent manner. The expression of hypoxia-inducible factor-1α (HIF-1α), hexokinase 2 (HK2), and glucose transporter 1 (GLUT-1), critical for the Warburg effect and glucose metabolism, was considerably reduced after the inhibitor treatments. Moreover, inhibiting PARP1 activation reduced phosphorylated AKT (p-AKT) and mTOR (p-mTOR) levels. In conclusion, our study revealed that PARP1 inhibition decelerates the Warburg effect in colorectal cancer cells, likely through the AKT/mTOR/HIF-1α pathway.
{"title":"Poly-ADP-ribosylation modulated by poly(ADP-ribose) polymerase 1 is associated with glucose metabolism in colorectal cancer cells","authors":"Chenxuan Zhang , Peng Wang , Jia Yu , Jianhui Yuan , Lilong Zhang , Man Li","doi":"10.1016/j.tranon.2025.102623","DOIUrl":"10.1016/j.tranon.2025.102623","url":null,"abstract":"<div><div>The preference of cancer cells to generate energy from glycolysis for rapid cell proliferation is called the Warburg effect. Poly(ADP-ribose) polymerase 1 (PARP1) performs various cellular functions, including poly-ADP-ribosylation and DNA repair. In the present study, we investigated the novel effects and mechanisms of PARP1 inhibition on glucose metabolism in colorectal cancer cells under hypoxia. We subjected Caco-2 and LoVo cancer cell lines to a concentration gradient of PARP1 inhibitor in a hypoxic environment induced with a tri-gas incubator (5 % CO<sub>2</sub>, 1 % O<sub>2</sub>, 94 % N<sub>2</sub>). Inhibiting PARP1 activation attenuated Poly-ADP-ribosylation, increasing the NAD<sup>+</sup>/NADH ratio. High concentrations of PARP1 significantly reduced the glucose consumption rate of the treated cells, while PARP1 inhibition depressed cell progression in a concentration-dependent manner. The expression of hypoxia-inducible factor-1α (HIF-1α), hexokinase 2 (HK2), and glucose transporter 1 (GLUT-1), critical for the Warburg effect and glucose metabolism, was considerably reduced after the inhibitor treatments. Moreover, inhibiting PARP1 activation reduced phosphorylated AKT (p-AKT) and mTOR (p-mTOR) levels. In conclusion, our study revealed that PARP1 inhibition decelerates the Warburg effect in colorectal cancer cells, likely through the AKT/mTOR/HIF-1α pathway.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102623"},"PeriodicalIF":5.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678790","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 : 2025-12-03DOI: 10.1016/j.tranon.2025.102629
Boopathi Subramaniyan , Yahui Li , Zhaohui Xiong , Chorlada Paiboonrungruang , Candice Bui-Linh , Francis Spitz , Xiaoxin Chen
Mutations in nuclear factor erythroid 2–related factor 2 (NFE2L2 or NRF2) occur in 10–22 % of esophageal squamous cell carcinoma (ESCC) cases and result in NRF2 activation, promoting tumor progression, and therapeutic resistance. Although previous studies suggested a link between NRF2 and kinases, specific kinases responsive to NRF2 activation remain to be fully identified. Using protein phosphorylation profiling and kinase activity profiling, we identified phosphatidylinositol 3-kinase (PI3K) pathway as a downstream effector in NRF2W24C-KYSE70 cells compared to isogenic NRF2null-KYSE70 cells. AREG, pEGFR, PIK3CA, pAKT, p-S6, and p-PTEN were downregulated in NRF2 deficient cells. Notably, NRF2 deficiency sensitized ESCC cells to EGFR, PIK3CA, and AKT inhibitors. Co-treatment with Alpelisib (a PIK3CA inhibitor) and Pyrimethamine (an NRF2 inhibitor) synergistically suppressed the growth of NRF2W24C-KYSE70 and NRF2D77V-KYSE180 cells. In vivo, NRF2 activation in the esophageal epithelium of Keap1-/- and Sox2CreER;LSL-Nrf2E79Q/+ mice resulted in upregulation of pAKT, p-mTOR, and pS6. In human ESCC tissues, expression of pNRF2 (an active form of NRF2) was positively associated with that of pAKT and p-mTOR. Furthermore, co-treatment with Pyrimethamine and Alpelisib significantly inhibited hyperproliferation and hyperkeratinization in the esophageal epithelium of Sox2CreER;LSL-Nrf2E79Q/+mice. Together, our data demonstrates the PI3K pathway as a downstream effector of NRF2 activation in the esophagus, and co-targeting of NRF2 and the PI3K pathway may offer a promising therapeutic strategy for NRF2Mut ESCC.
{"title":"The PI3K pathway is a downstream effector of NRF2 activation in the esophagus","authors":"Boopathi Subramaniyan , Yahui Li , Zhaohui Xiong , Chorlada Paiboonrungruang , Candice Bui-Linh , Francis Spitz , Xiaoxin Chen","doi":"10.1016/j.tranon.2025.102629","DOIUrl":"10.1016/j.tranon.2025.102629","url":null,"abstract":"<div><div>Mutations in nuclear factor erythroid 2–related factor 2 (<em>NFE2L2</em> or <em>NRF2</em>) occur in 10–22 % of esophageal squamous cell carcinoma (ESCC) cases and result in NRF2 activation, promoting tumor progression, and therapeutic resistance. Although previous studies suggested a link between NRF2 and kinases, specific kinases responsive to NRF2 activation remain to be fully identified. Using protein phosphorylation profiling and kinase activity profiling, we identified phosphatidylinositol 3-kinase (PI3K) pathway as a downstream effector in NRF2<sup>W24C</sup>-KYSE70 cells compared to isogenic NRF2<sup>null</sup>-KYSE70 cells. AREG, pEGFR, PIK3CA, pAKT, p-S6, and p-PTEN were downregulated in NRF2 deficient cells. Notably, NRF2 deficiency sensitized ESCC cells to EGFR, PIK3CA, and AKT inhibitors. Co-treatment with Alpelisib (a PIK3CA inhibitor) and Pyrimethamine (an NRF2 inhibitor) synergistically suppressed the growth of NRF2<sup>W24C</sup>-KYSE70 and NRF2<sup>D77V</sup>-KYSE180 cells. <em>In vivo</em>, NRF2 activation in the esophageal epithelium of <em>Keap1<sup>-/-</sup></em> and <em>Sox2CreER;LSL-Nrf2<sup>E79Q/+</sup></em> mice resulted in upregulation of pAKT, p-mTOR, and pS6. In human ESCC tissues, expression of pNRF2 (an active form of NRF2) was positively associated with that of pAKT and p-mTOR. Furthermore, co-treatment with Pyrimethamine and Alpelisib significantly inhibited hyperproliferation and hyperkeratinization in the esophageal epithelium of <em>Sox2CreER;LSL-Nrf2<sup>E79Q/+</sup></em>mice. Together, our data demonstrates the PI3K pathway as a downstream effector of NRF2 activation in the esophagus, and co-targeting of NRF2 and the PI3K pathway may offer a promising therapeutic strategy for NRF2<sup>Mut</sup> ESCC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102629"},"PeriodicalIF":5.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678825","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 : 2025-12-03DOI: 10.1016/j.tranon.2025.102626
Yuchen Shi , Jiazhu Sun , Kai Yu , Dingheng Lu, Xinyang Niu, Yuxiao Li, Suyuelin Huang, Jindan Luo, Xiao Wang, Xueyou Ma, Jiangfeng Li, Yufan Ying, Liping Xie, Ben Liu
Piwi-interacting RNAs (piRNAs), while crucial for genomic integrity in germline cells, remain poorly characterized in somatic cancers. This study identifies piR-43452 as a significantly downregulated piRNA in bladder cancer (BCa), with loss of expression correlating clinically with muscle invasion and lymph node metastasis. Through assays in vitro and in vivo, we demonstrate that piR-43452 acts as a potent tumor suppressor, inhibiting BCa cell proliferation, migration, and xenograft growth while promoting apoptosis. Mechanistically, we identified that piR-43452 directly binds the 3′UTR of LRP1 mRNA and recruits the GTSF1/PIWIL4 complex, which enhances target cleavage through GTSF1-dependent conformational activation. This post-transcriptional regulation led to significant LRP1 suppression, subsequently inhibiting proliferation and restoring chemosensitivity. Our findings establish a novel piRNA-guided mechanism for overcoming chemoresistance and suggest that targeting the piR-43452/GTSF1/PIWIL4/LRP1 axis may provide therapeutic benefit in gemcitabine-resistant BCa.
{"title":"piR-43452 suppresses bladder cancer progression and enhances gemcitabine sensitivity via GTSF1/PIWIL4-mediated LRP1 mRNA destabilization","authors":"Yuchen Shi , Jiazhu Sun , Kai Yu , Dingheng Lu, Xinyang Niu, Yuxiao Li, Suyuelin Huang, Jindan Luo, Xiao Wang, Xueyou Ma, Jiangfeng Li, Yufan Ying, Liping Xie, Ben Liu","doi":"10.1016/j.tranon.2025.102626","DOIUrl":"10.1016/j.tranon.2025.102626","url":null,"abstract":"<div><div>Piwi-interacting RNAs (piRNAs), while crucial for genomic integrity in germline cells, remain poorly characterized in somatic cancers. This study identifies piR-43452 as a significantly downregulated piRNA in bladder cancer (BCa), with loss of expression correlating clinically with muscle invasion and lymph node metastasis. Through assays <em>in vitro</em> and <em>in vivo</em>, we demonstrate that piR-43452 acts as a potent tumor suppressor, inhibiting BCa cell proliferation, migration, and xenograft growth while promoting apoptosis. Mechanistically, we identified that piR-43452 directly binds the 3′UTR of LRP1 mRNA and recruits the GTSF1/PIWIL4 complex, which enhances target cleavage through GTSF1-dependent conformational activation. This post-transcriptional regulation led to significant LRP1 suppression, subsequently inhibiting proliferation and restoring chemosensitivity. Our findings establish a novel piRNA-guided mechanism for overcoming chemoresistance and suggest that targeting the piR-43452/GTSF1/PIWIL4/LRP1 axis may provide therapeutic benefit in gemcitabine-resistant BCa.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102626"},"PeriodicalIF":5.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678706","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 : 2025-12-03DOI: 10.1016/j.tranon.2025.102618
Ki-Kwang Oh , Goo-Hyun Kwon, Kyeong Jin Lee, Jung-A Eom , Dong Joon Kim, Ki-Tae Suk
Background
Non-alcoholic fatty liver disease (NAFLD) is involved in non-alcoholic steatohepatitis (NASH), liver cirrhosis (LC), and even hepatocellular carcinoma (HCC). Hence, this study was to elucidate nuanced key mechanism(s), target(s), and Natural Indole-Derived Molecules (NIDMs) against NAFLD-derived HCC.
Methods
The NIDMs were retrieved by Natural Product Activity & Species Source Database (NPASS). The protein-protein interaction (PPI) networks, bubble plot on key signaling pathways, etiological spectrum-signaling pathways-targets-indoles (ESTI) networks, the verification of toxicity on key NIDMs, and MDE (Molecular Docking Evaluation) were performed with integrating perspective.
Results
The 141 NIDMs were identified by NPASS and SwissADME, suggesting that the NIDMs were associated with Similarity Ensemble Approach (SEA; 845 targets) and SwissTargetPrediction (STP; 1107 targets). On PPI analysis, JUN was the uppermost target with the highest DV (Degree Value). A bubble plot based on rich factor constructed to identify key mechanism(s), suggesting that AGE-RAGE signaling pathway in diabetic complications might be key antagonistic mode to hinder the spontaneous progression of NAFLD. The key targets were JUN, and AGTR1 on AGE-RAGE signaling pathway in diabetic complications, binding most stably to Marinacarboline D, and Fumitremorgin F, respectively.
Conclusions
In closing, this study provides critical insights into the key mechanisms, targets, and NIDMs that may impede etiological spectrum of NAFLD.
{"title":"A roadmap to unveil the mechanism(s) of natural indole-derived molecules against NAFLD-derived HCC via systems pharmacology","authors":"Ki-Kwang Oh , Goo-Hyun Kwon, Kyeong Jin Lee, Jung-A Eom , Dong Joon Kim, Ki-Tae Suk","doi":"10.1016/j.tranon.2025.102618","DOIUrl":"10.1016/j.tranon.2025.102618","url":null,"abstract":"<div><h3>Background</h3><div>Non-alcoholic fatty liver disease (NAFLD) is involved in non-alcoholic steatohepatitis (NASH), liver cirrhosis (LC), and even hepatocellular carcinoma (HCC). Hence, this study was to elucidate nuanced key mechanism(s), target(s), and Natural Indole-Derived Molecules (NIDMs) against NAFLD-derived HCC.</div></div><div><h3>Methods</h3><div>The NIDMs were retrieved by Natural Product Activity & Species Source Database (NPASS). The protein-protein interaction (PPI) networks, bubble plot on key signaling pathways, etiological spectrum-signaling pathways-targets-indoles (ESTI) networks, the verification of toxicity on key NIDMs, and MDE (Molecular Docking Evaluation) were performed with integrating perspective.</div></div><div><h3>Results</h3><div>The 141 NIDMs were identified by NPASS and SwissADME, suggesting that the NIDMs were associated with Similarity Ensemble Approach (SEA; 845 targets) and SwissTargetPrediction (STP; 1107 targets). On PPI analysis, JUN was the uppermost target with the highest DV (Degree Value). A bubble plot based on rich factor constructed to identify key mechanism(s), suggesting that AGE-RAGE signaling pathway in diabetic complications might be key antagonistic mode to hinder the spontaneous progression of NAFLD. The key targets were JUN, and AGTR1 on AGE-RAGE signaling pathway in diabetic complications, binding most stably to Marinacarboline D, and Fumitremorgin F, respectively.</div></div><div><h3>Conclusions</h3><div>In closing, this study provides critical insights into the key mechanisms, targets, and NIDMs that may impede etiological spectrum of NAFLD.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102618"},"PeriodicalIF":5.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678674","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 : 2025-12-02DOI: 10.1016/j.tranon.2025.102624
Jianhui Yang , Jiang Liu , Zeyin Rong , Zhen Tan , Wei Wang , Qingcai Meng , Miaoyan Wei , Jie Hua , Bo Zhang , Xianjun Yu , Jin Xu , Chen Liang
Background
Pancreatic ductal adenocarcinoma (PDAC) exhibits profound chemoresistance and metastasis, driving its dismal prognosis. Gemcitabine (GEM) resistance remains a critical barrier, necessitating exploration of metabolic regulators like choline phosphotransferase 1 (CHPT1) and ferroptosis in PDAC therapy.
Method
GEM-resistant PDAC cells were generated through stepwise induction. Metabolomics, RNA sequencing, and functional assays (CCK-8, EdU, Transwell) identified CHPT’s role. CHPT1 and SLC7A11 were genetically modulated using lentiviral vectors. Xenograft models assessed tumor growth.
Results
CHPT1 was downregulated in PDAC tissues and GEM-resistant cells. Restoring CHPT1 suppressed proliferation, migration, and epithelial–mesenchymal transition while enhancing GEM sensitivity. Mechanistically, CHPT1 recruited phosphatase PTPN1 to dephosphorylate STAT3 at Y705, inhibiting SLC7A11 transcription and triggering ferroptosis via lipid peroxidation. PTPN1 knockdown abolished CHPT1’s tumor-suppressive effects. Combining ferroptosis inducers (e.g., Erastin) with GEM synergistically inhibited tumor growth in vitro and in vivo.
Conclusion
The CHPT1-pSTAT3-SLC7A11 axis governs ferroptosis-dependent chemoresistance in PDAC. Dual targeting of CHPT1 and ferroptosis pathways represents a promising strategy to overcome GEM resistance, highlighting metabolic-kinase crosstalk as a therapeutic vulnerability.
{"title":"The CHPT-pSTAT3-SLC7A11 signaling axis controls progression and ferroptosis susceptibility of pancreatic cancer","authors":"Jianhui Yang , Jiang Liu , Zeyin Rong , Zhen Tan , Wei Wang , Qingcai Meng , Miaoyan Wei , Jie Hua , Bo Zhang , Xianjun Yu , Jin Xu , Chen Liang","doi":"10.1016/j.tranon.2025.102624","DOIUrl":"10.1016/j.tranon.2025.102624","url":null,"abstract":"<div><h3>Background</h3><div>Pancreatic ductal adenocarcinoma (PDAC) exhibits profound chemoresistance and metastasis, driving its dismal prognosis. Gemcitabine (GEM) resistance remains a critical barrier, necessitating exploration of metabolic regulators like choline phosphotransferase 1 (CHPT1) and ferroptosis in PDAC therapy.</div></div><div><h3>Method</h3><div>GEM-resistant PDAC cells were generated through stepwise induction. Metabolomics, RNA sequencing, and functional assays (CCK-8, EdU, Transwell) identified CHPT’s role. CHPT1 and SLC7A11 were genetically modulated using lentiviral vectors. Xenograft models assessed tumor growth.</div></div><div><h3>Results</h3><div>CHPT1 was downregulated in PDAC tissues and GEM-resistant cells. Restoring CHPT1 suppressed proliferation, migration, and epithelial–mesenchymal transition while enhancing GEM sensitivity. Mechanistically, CHPT1 recruited phosphatase PTPN1 to dephosphorylate STAT3 at Y705, inhibiting SLC7A11 transcription and triggering ferroptosis via lipid peroxidation. PTPN1 knockdown abolished CHPT1’s tumor-suppressive effects. Combining ferroptosis inducers (e.g., Erastin) with GEM synergistically inhibited tumor growth in vitro and in vivo.</div></div><div><h3>Conclusion</h3><div>The CHPT1-pSTAT3-SLC7A11 axis governs ferroptosis-dependent chemoresistance in PDAC. Dual targeting of CHPT1 and ferroptosis pathways represents a promising strategy to overcome GEM resistance, highlighting metabolic-kinase crosstalk as a therapeutic vulnerability.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102624"},"PeriodicalIF":5.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669829","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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