Pub Date : 2025-12-01DOI: 10.1016/j.tranon.2025.102619
Zhihui Mi , Hui Guan , Guodong Zhang , Dongyang Li , Yang Yu , Jialin Qu
The success of cancer immunotherapy is hampered by the lack of dynamic models that can predict patient-specific responses and guide the development of novel treatments. Static biomarkers, such as PD-L1 expression and tumor mutational burden, often fail to capture the complexity of the tumor-immune dialogue. Patient-derived tumor organoids (PDTOs) have emerged as a revolutionary ex vivo platform that bridges this gap. This review outlines the evolution of PDTOs from simple epithelial cultures to sophisticated, immune-competent "avatars" that faithfully recapitulate the patient's tumor microenvironment (TME). We critically discuss the key methodologies for reconstructing the TME, including "add-in" co-culture systems with diverse immune and stromal cells (e.g., T-cells, MDSCs, CAFs, neutrophils) and "all-in-one" approaches that preserve the native immune ecosystem. Furthermore, we highlight the expanding role of these advanced models beyond predicting checkpoint inhibitor efficacy. We showcase their groundbreaking applications as core development platforms for next-generation immunotherapies, including CAR-T cell therapy and the validation of personalized neoantigen-based vaccines. While acknowledging the significant translational challenges that remain, we conclude that immune-competent PDTOs represent an indispensable tool poised to accelerate the new era of precision immuno-oncology.
{"title":"From benchside avatars to bedside breakthroughs: Patient-derived organoids in the new era of cancer immunotherapy","authors":"Zhihui Mi , Hui Guan , Guodong Zhang , Dongyang Li , Yang Yu , Jialin Qu","doi":"10.1016/j.tranon.2025.102619","DOIUrl":"10.1016/j.tranon.2025.102619","url":null,"abstract":"<div><div>The success of cancer immunotherapy is hampered by the lack of dynamic models that can predict patient-specific responses and guide the development of novel treatments. Static biomarkers, such as PD-L1 expression and tumor mutational burden, often fail to capture the complexity of the tumor-immune dialogue. Patient-derived tumor organoids (PDTOs) have emerged as a revolutionary ex vivo platform that bridges this gap. This review outlines the evolution of PDTOs from simple epithelial cultures to sophisticated, immune-competent \"avatars\" that faithfully recapitulate the patient's tumor microenvironment (TME). We critically discuss the key methodologies for reconstructing the TME, including \"add-in\" co-culture systems with diverse immune and stromal cells (e.g., T-cells, MDSCs, CAFs, neutrophils) and \"all-in-one\" approaches that preserve the native immune ecosystem. Furthermore, we highlight the expanding role of these advanced models beyond predicting checkpoint inhibitor efficacy. We showcase their groundbreaking applications as core development platforms for next-generation immunotherapies, including CAR-T cell therapy and the validation of personalized neoantigen-based vaccines. While acknowledging the significant translational challenges that remain, we conclude that immune-competent PDTOs represent an indispensable tool poised to accelerate the new era of precision immuno-oncology.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102619"},"PeriodicalIF":5.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661742","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 : 2025-12-01DOI: 10.1016/j.tranon.2025.102620
Jiayi He , Shuo Ma , Shougang Kuai , Shaoqing Ju
Background
Gastric cancer (GC) remains a major cause of cancer-related mortality globally, largely due to the absence of reliable non-invasive biomarkers for early detection. Circular RNAs (circRNAs), characterized by covalently closed-loop structures, stability, and detectability in circulation, have emerged as promising liquid biopsy candidates.
Methods
circAHSA1 (hsa_circ_0032777) was identified through GEO dataset screening (GSE121445) and validated in GC tissues, serum, and cell lines using qRT-PCR with optimized internal reference selection. Diagnostic performance was assessed using ROC analysis and DeLong tests, evaluating circAHSA1 alone and in combination with CEA, CA199, and CA724. Biological functions were examined through proliferation, apoptosis, migration, and invasion assays. Subcellular localization and potential downstream miRNA interactions were analyzed using nuclear–cytoplasmic fractionation and multi-database bioinformatic prediction.
Results
circAHSA1 expression was significantly elevated in GC tissues, serum, and cell lines, and correlated with lymph node metastasis, differentiation status, and TNM stage. Serum circAHSA1 effectively discriminated GC from healthy controls (AUC = 0.787) and gastritis patients (AUC = 0.752), outperforming conventional markers, with statistical superiority confirmed by DeLong analysis. Combined detection further improved diagnostic accuracy (AUC = 0.871). Functionally, silencing circAHSA1 suppressed GC cell proliferation, migration, and invasion while enhancing apoptosis and inducing cell-cycle arrest. Bioinformatic analysis suggested miR-647 and miR-661 as potential downstream targets.
Conclusions
circAHSA1 is a stable, GC-specific circulating biomarker with both diagnostic and functional relevance. These findings support circAHSA1 as a promising candidate for liquid biopsy-based GC detection and a potential therapeutic target.
{"title":"Circular RNA circAHSA1 serves as a stable serum biomarker for the diagnosis and progression of gastric cancer","authors":"Jiayi He , Shuo Ma , Shougang Kuai , Shaoqing Ju","doi":"10.1016/j.tranon.2025.102620","DOIUrl":"10.1016/j.tranon.2025.102620","url":null,"abstract":"<div><h3>Background</h3><div>Gastric cancer (GC) remains a major cause of cancer-related mortality globally, largely due to the absence of reliable non-invasive biomarkers for early detection. Circular RNAs (circRNAs), characterized by covalently closed-loop structures, stability, and detectability in circulation, have emerged as promising liquid biopsy candidates.</div></div><div><h3>Methods</h3><div>circAHSA1 (hsa_circ_0032777) was identified through GEO dataset screening (GSE121445) and validated in GC tissues, serum, and cell lines using qRT-PCR with optimized internal reference selection. Diagnostic performance was assessed using ROC analysis and DeLong tests, evaluating circAHSA1 alone and in combination with CEA, CA199, and CA724. Biological functions were examined through proliferation, apoptosis, migration, and invasion assays. Subcellular localization and potential downstream miRNA interactions were analyzed using nuclear–cytoplasmic fractionation and multi-database bioinformatic prediction.</div></div><div><h3>Results</h3><div>circAHSA1 expression was significantly elevated in GC tissues, serum, and cell lines, and correlated with lymph node metastasis, differentiation status, and TNM stage. Serum circAHSA1 effectively discriminated GC from healthy controls (AUC = 0.787) and gastritis patients (AUC = 0.752), outperforming conventional markers, with statistical superiority confirmed by DeLong analysis. Combined detection further improved diagnostic accuracy (AUC = 0.871). Functionally, silencing circAHSA1 suppressed GC cell proliferation, migration, and invasion while enhancing apoptosis and inducing cell-cycle arrest. Bioinformatic analysis suggested miR-647 and miR-661 as potential downstream targets.</div></div><div><h3>Conclusions</h3><div>circAHSA1 is a stable, GC-specific circulating biomarker with both diagnostic and functional relevance. These findings support circAHSA1 as a promising candidate for liquid biopsy-based GC detection and a potential therapeutic target.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102620"},"PeriodicalIF":5.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661664","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 : 2025-11-29DOI: 10.1016/j.tranon.2025.102607
Hsinyi Lin , Zimin Zhao , Yao Ma , Xiangchao Shi , Limei Guo , Junwei Wang , Wei Fu , Xin Zhou
Background
This study aims to evaluate the prognostic value of tumor macroscopic morphology in colorectal cancer (CRC) and understand the molecular mechanism behind different tumor morphologies.
Methods
642 eligible patients were enrolled in this study, including 335 patients in the prospective study and 307 patients in the retrospective study. CRCs were categorized into protruded, ulcerative, and infiltrative types according to our morphological classification, and their clinicopathological features and prognosis were analyzed. Furthermore, bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq) and immunohistochemistry were performed to map the tumor microenvironment of different tumor morphologies.
Results
In the prospective cohort, CRC with infiltrative type were significantly associated with unfavorable clinicopathological characteristics and poor survival compared with ulcerative type and protruded type. Bulk RNA sequencing revealed that the infiltrative type correlated with higher expression of fibroblast activation protein-α (FAP), periostin and platelet endothelial cell adhesion molecule-1 (PECAM-1), which corresponded with elevated cell proportions of stromal cells and endothelial cells in scRNA-seq. Additionally, a retrospective cohort was conducted to assess the value of preoperative endoscopic morphology and radiological morphology, both independently associated with disease-free survival (DFS).
Conclusion
We proposed a revised tumor macroscopic morphology classification system in CRC. The infiltrative type is associated with poorer clinical outcomes, characterized by increased cancer-associated fibroblast (CAF) infiltration and enhanced angiogenesis compared with other types. Importantly, when expanded to endoscopy and CT preoperatively, both endoscopic and radiological morphology can serve as preoperative predictors of DFS.
{"title":"The prognostic value of tumor macroscopic morphology in colorectal cancer","authors":"Hsinyi Lin , Zimin Zhao , Yao Ma , Xiangchao Shi , Limei Guo , Junwei Wang , Wei Fu , Xin Zhou","doi":"10.1016/j.tranon.2025.102607","DOIUrl":"10.1016/j.tranon.2025.102607","url":null,"abstract":"<div><h3>Background</h3><div>This study aims to evaluate the prognostic value of tumor macroscopic morphology in colorectal cancer (CRC) and understand the molecular mechanism behind different tumor morphologies.</div></div><div><h3>Methods</h3><div>642 eligible patients were enrolled in this study, including 335 patients in the prospective study and 307 patients in the retrospective study. CRCs were categorized into protruded, ulcerative, and infiltrative types according to our morphological classification, and their clinicopathological features and prognosis were analyzed. Furthermore, bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq) and immunohistochemistry were performed to map the tumor microenvironment of different tumor morphologies.</div></div><div><h3>Results</h3><div>In the prospective cohort, CRC with infiltrative type were significantly associated with unfavorable clinicopathological characteristics and poor survival compared with ulcerative type and protruded type. Bulk RNA sequencing revealed that the infiltrative type correlated with higher expression of fibroblast activation protein-α (FAP), periostin and platelet endothelial cell adhesion molecule-1 (PECAM-1), which corresponded with elevated cell proportions of stromal cells and endothelial cells in scRNA-seq. Additionally, a retrospective cohort was conducted to assess the value of preoperative endoscopic morphology and radiological morphology, both independently associated with disease-free survival (DFS).</div></div><div><h3>Conclusion</h3><div>We proposed a revised tumor macroscopic morphology classification system in CRC. The infiltrative type is associated with poorer clinical outcomes, characterized by increased cancer-associated fibroblast (CAF) infiltration and enhanced angiogenesis compared with other types. Importantly, when expanded to endoscopy and CT preoperatively, both endoscopic and radiological morphology can serve as preoperative predictors of DFS.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102607"},"PeriodicalIF":5.0,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623667","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 : 2025-11-29DOI: 10.1016/j.tranon.2025.102612
Yilv Lv , Zhitao Gu , Kunping Li , Teng Mao , Xuefei Zhang , Ning Xu , Wentao Fang , Qiangling Sun
Objective
To identify molecular determinants of tumor aggressiveness in TETs and to elucidate their functional roles and underlying mechanisms in tumor progression.
Methods
We performed proteomic profiling using data-independent acquisition mass spectrometry on 40 TET samples and their paired adjacent normal tissues to explore potential molecular differences. TETs were stratified into high-risk (WHO types B2, B3, and thymic carcinoma) and low-risk (types A, AB, and B1) groups based on histological classification. Gene set enrichment analysis (GSEA) was applied to the proteomic data to delineate pathways enriched in high-risk tumors. A validation cohort comprising 164 TET patients, along with 6 non-TET controls, was analyzed to assess Galectin-7 expression by immunohistochemistry and to evaluate its prognostic value. To further explore the biological role of Galectin-7, functional assays were performed in Tc1889 cells following Galectin-7 overexpression.
Results
Proteomic analysis revealed Galectin-7 as a highly upregulated protein in high-risk TETs. GSEA analysis identified enrichment of mitochondrial and extracellular matrix-related pathways in high-risk tumors. Immunohistochemistry showed Galectin-7 expression in 82 % of high-risk TETs and only 13 % of low-risk TETs (p < 0.001), with higher expression correlating with advanced tumor stage and reduced progression-free survival. Functional assays demonstrated that Tc1889 cells with Galectin-7 overexpression exhibited enhanced proliferation and invasion. Additionally, MAPK signaling pathway activation was observed in Galectin-7-overexpressing cells.
Conclusions
Galectin-7 is a potential biomarker for aggressive TETs, with expression levels associated with features of poor prognosis. These findings provide insight into TET biology and support further exploration of Galectin-7 in tumor stratification and therapeutic research.
{"title":"Galectin-7 as a biomarker for aggressiveness and poor prognosis in thymic epithelial tumors","authors":"Yilv Lv , Zhitao Gu , Kunping Li , Teng Mao , Xuefei Zhang , Ning Xu , Wentao Fang , Qiangling Sun","doi":"10.1016/j.tranon.2025.102612","DOIUrl":"10.1016/j.tranon.2025.102612","url":null,"abstract":"<div><h3>Objective</h3><div>To identify molecular determinants of tumor aggressiveness in TETs and to elucidate their functional roles and underlying mechanisms in tumor progression.</div></div><div><h3>Methods</h3><div>We performed proteomic profiling using data-independent acquisition mass spectrometry on 40 TET samples and their paired adjacent normal tissues to explore potential molecular differences. TETs were stratified into high-risk (WHO types B2, B3, and thymic carcinoma) and low-risk (types A, AB, and B1) groups based on histological classification. Gene set enrichment analysis (GSEA) was applied to the proteomic data to delineate pathways enriched in high-risk tumors. A validation cohort comprising 164 TET patients, along with 6 non-TET controls, was analyzed to assess Galectin-7 expression by immunohistochemistry and to evaluate its prognostic value. To further explore the biological role of Galectin-7, functional assays were performed in Tc1889 cells following Galectin-7 overexpression.</div></div><div><h3>Results</h3><div>Proteomic analysis revealed Galectin-7 as a highly upregulated protein in high-risk TETs. GSEA analysis identified enrichment of mitochondrial and extracellular matrix-related pathways in high-risk tumors. Immunohistochemistry showed Galectin-7 expression in 82 % of high-risk TETs and only 13 % of low-risk TETs (<em>p</em> < 0.001), with higher expression correlating with advanced tumor stage and reduced progression-free survival. Functional assays demonstrated that Tc1889 cells with Galectin-7 overexpression exhibited enhanced proliferation and invasion. Additionally, MAPK signaling pathway activation was observed in Galectin-7-overexpressing cells.</div></div><div><h3>Conclusions</h3><div>Galectin-7 is a potential biomarker for aggressive TETs, with expression levels associated with features of poor prognosis. These findings provide insight into TET biology and support further exploration of Galectin-7 in tumor stratification and therapeutic research.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102612"},"PeriodicalIF":5.0,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623610","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}
PARP inhibitors have revolutionized ovarian cancer treatment, with benefits strongly linked to the presence of Homologous Recombination Deficiency (HRD). Although HRD testing was originally conducted on centralized platforms, there is growing demand for scalable, accessible, and robust solutions capable of supporting expanded clinical utilization. In the present study, a decentralized NGS-based assay was compared for its ability to effectively identify HRD positive patients when compared to the reference assay as well as other testing platforms.
Eighty-two cases of ovarian cancer patients previously tested using the reference HRD assay (Myriad MyChoice® CDx assay) were evaluated by an NGS based HRD assay, the 1021-HRD assay (GenePlus), that provides genomic instability (GI) analysis along with tumor molecular profiling. HRD status, GI status (referred to as HRD-score), and even BRCA1/2 mutation detection were assessed for concordance with the reference test and the analytical accuracy of the assay was calculated. Additionally, GI alignment across alternative HRD testing platforms was examined. Finally, the association between key tumor alterations and the HRD status was evaluated.
The 1021-HRD assay demonstrated an overall HRD classification agreement of approximately 92.68 % (κ = 0.841) in comparison to the reference method, as evidenced by the results, with 81.25 % specificity and 100 % sensitivity. These features generally suggest consistent performance, with only minor discrepancies observed. The BRCA1/2 alterations detected were 97.56 % in agreement with the approved assay. The Pearson r value of 0.878 indicates a strong correlation between the GI values obtained. The assay's capacity to detect non-BRCA1/2 HRD phenotypes was verified by the observation that 55.56 % of BRCA-wildtype malignancies were HRD-positive. Of particular interest, combining molecular profiling with GI analysis, the assay identified additional actionable alterations in 65 % of the cases, revealing clinically relevant biomarkers beyond the homologous recombination pathway. This wide-ranging approach may provide more diagnostic and therapeutic insight than HRD testing alone.
In conclusion, the 1021-HRD assay is a dependable, decentralized alternative for HRD testing. It can provide a more comprehensive genomic characterization and exhibits remarkable analytical concordance with current standards. Its combined format and accessibility render it well-suited for real-world use in personalized ovarian cancer care. Its additional capacity to reveal more extensive tumor genomic alterations improves clinical decision-making and underscores the importance of integrating HRD scoring with comprehensive molecular profiling in personalized oncology.
{"title":"Evaluation of the 1021-HRD assay compared to established HRD testing platforms in ovarian cancer","authors":"Eirini Papadopoulou , Elena Fountzilas , Vasiliki Metaxa-Mariatou , Aikaterini Tsantikidi , Georgios Tsaousis , Angeliki Meintani , Chrysiida Florou-Chatzigiannidou , Stella Maxouri , Konstantinos Papazisis , Theofanis Floros , Christos Papadimitriou , Eleni Timotheadou , Kyriaki Papadopoulou , Athanasios Papathanasiou , Dimitrios Grigoriadis , Xiaorui Fu , Xunmei Zheng , Yun Xing , Xinhua Du , Andreea Truican , George Nasioulas","doi":"10.1016/j.tranon.2025.102621","DOIUrl":"10.1016/j.tranon.2025.102621","url":null,"abstract":"<div><div>PARP inhibitors have revolutionized ovarian cancer treatment, with benefits strongly linked to the presence of Homologous Recombination Deficiency (HRD). Although HRD testing was originally conducted on centralized platforms, there is growing demand for scalable, accessible, and robust solutions capable of supporting expanded clinical utilization. In the present study, a decentralized NGS-based assay was compared for its ability to effectively identify HRD positive patients when compared to the reference assay as well as other testing platforms.</div><div>Eighty-two cases of ovarian cancer patients previously tested using the reference HRD assay (Myriad MyChoice® CDx assay) were evaluated by an NGS based HRD assay, the 1021-HRD assay (GenePlus), that provides genomic instability (GI) analysis along with tumor molecular profiling. HRD status, GI status (referred to as HRD-score), and even <em>BRCA1/2</em> mutation detection were assessed for concordance with the reference test and the analytical accuracy of the assay was calculated. Additionally, GI alignment across alternative HRD testing platforms was examined. Finally, the association between key tumor alterations and the HRD status was evaluated.</div><div>The 1021-HRD assay demonstrated an overall HRD classification agreement of approximately 92.68 % (κ = 0.841) in comparison to the reference method, as evidenced by the results, with 81.25 % specificity and 100 % sensitivity. These features generally suggest consistent performance, with only minor discrepancies observed. The <em>BRCA1/2</em> alterations detected were 97.56 % in agreement with the approved assay. The Pearson r value of 0.878 indicates a strong correlation between the GI values obtained. The assay's capacity to detect non-<em>BRCA1/2</em> HRD phenotypes was verified by the observation that 55.56 % of <em>BRCA</em>-wildtype malignancies were HRD-positive. Of particular interest, combining molecular profiling with GI analysis, the assay identified additional actionable alterations in 65 % of the cases, revealing clinically relevant biomarkers beyond the homologous recombination pathway. This wide-ranging approach may provide more diagnostic and therapeutic insight than HRD testing alone.</div><div>In conclusion, the 1021-HRD assay is a dependable, decentralized alternative for HRD testing. It can provide a more comprehensive genomic characterization and exhibits remarkable analytical concordance with current standards. Its combined format and accessibility render it well-suited for real-world use in personalized ovarian cancer care. Its additional capacity to reveal more extensive tumor genomic alterations improves clinical decision-making and underscores the importance of integrating HRD scoring with comprehensive molecular profiling in personalized oncology.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102621"},"PeriodicalIF":5.0,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623666","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 : 2025-11-25DOI: 10.1016/j.tranon.2025.102577
Hui Li , Huiting Wei , Tiantian Zhen , Huabin Gao , Huicong Liu , Shuai Zheng , Huijuan Shi , Jiangtao Liang , Fenfen Zhang , Jiecheng Ye , Gengpeng Lin , Anjia Han
Background
Overcoming osimertinib resistance in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) is challenging due to unclear mechanisms. We previously reported a NSCLC case with EGFR mutations progressed on osimertinib therapy, revealing a novel NOTCH2-NTRK1 fusion gene in the plasma and tumor tissue. Although the NTRK gene fusion has been identified in NSCLC and a range of tumor types, the role of NOTCH2-NTRK1 in osimertinib resistance is unclear.
Methods
We utilized both in vitro and in vivo models exhibiting NOTCH2-NTRK1 fusion positivity to explore the biological function of NOTCH2-NTRK1, as well as its role and mechanism in osimertinib resistance.
Results
The NOTCH2-NTRK1 fusion protein has been demonstrated to transform the human bronchial epithelial cell line BEAS-2B and promote the proliferation of NSCLC cells both in vitro and in vivo. It induces osimertinib resistance by activating MAPK and PI3K-AKT pathways. Phosphoproteomic analyses revealed a significant increase in the phosphorylation level of EGFR compared to the control group. Further investigations demonstrated that the NOTCH2-NTRK1 protein is capable of interacting with the EGFR protein. Protein molecular docking studies identified seven interacting sites between NOTCH2-NTRK1 and EGFR protein. Mutations within the region encompassing these seven interaction sites effectively reversed osimertinib resistance, leading to a significant reduction in the expression of key proteins within the MAPK and PI3K-AKT pathways. Notably, the interaction between NOTCH2-NTRK1 and EGFR was maintained even with combined osimertinib and entrectinib treatment.
Conclusion
Our study reveals a novel mechanism by which the NOTCH2-NTRK1 fusion confers resistance to osimertinib through its interaction with EGFR in NSCLC.
{"title":"Novel NOTCH2-NTRK1 fusion confers osimertinib resistance in EGFR-mutant non-small cell lung cancer by interacting with EGFR","authors":"Hui Li , Huiting Wei , Tiantian Zhen , Huabin Gao , Huicong Liu , Shuai Zheng , Huijuan Shi , Jiangtao Liang , Fenfen Zhang , Jiecheng Ye , Gengpeng Lin , Anjia Han","doi":"10.1016/j.tranon.2025.102577","DOIUrl":"10.1016/j.tranon.2025.102577","url":null,"abstract":"<div><h3>Background</h3><div>Overcoming osimertinib resistance in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) is challenging due to unclear mechanisms. We previously reported a NSCLC case with EGFR mutations progressed on osimertinib therapy, revealing a novel NOTCH2-NTRK1 fusion gene in the plasma and tumor tissue. Although the NTRK gene fusion has been identified in NSCLC and a range of tumor types, the role of NOTCH2-NTRK1 in osimertinib resistance is unclear.</div></div><div><h3>Methods</h3><div>We utilized both in vitro and in vivo models exhibiting NOTCH2-NTRK1 fusion positivity to explore the biological function of NOTCH2-NTRK1, as well as its role and mechanism in osimertinib resistance.</div></div><div><h3>Results</h3><div>The NOTCH2-NTRK1 fusion protein has been demonstrated to transform the human bronchial epithelial cell line BEAS-2B and promote the proliferation of NSCLC cells both in vitro and in vivo. It induces osimertinib resistance by activating MAPK and PI3K-AKT pathways. Phosphoproteomic analyses revealed a significant increase in the phosphorylation level of EGFR compared to the control group. Further investigations demonstrated that the NOTCH2-NTRK1 protein is capable of interacting with the EGFR protein. Protein molecular docking studies identified seven interacting sites between NOTCH2-NTRK1 and EGFR protein. Mutations within the region encompassing these seven interaction sites effectively reversed osimertinib resistance, leading to a significant reduction in the expression of key proteins within the MAPK and PI3K-AKT pathways. Notably, the interaction between NOTCH2-NTRK1 and EGFR was maintained even with combined osimertinib and entrectinib treatment.</div></div><div><h3>Conclusion</h3><div>Our study reveals a novel mechanism by which the NOTCH2-NTRK1 fusion confers resistance to osimertinib through its interaction with EGFR in NSCLC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102577"},"PeriodicalIF":5.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145606189","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 : 2025-11-25DOI: 10.1016/j.tranon.2025.102611
Eoghan O’Connor , Patricia Scanlan , Owen Patrick Smith , Melinda Halasz
Burkitt lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma, historically classified into three subtypes; endemic, sporadic and immunodeficiency associated BL. Accumulating evidence suggests that Epstein-Barr virus (EBV)-positive and EBV-negative BL represent biologically distinct entities. In this review, we aim to compare the clinicopathological and molecular differences in BL in the context of EBV status and chronic malaria infection.
From our review, clinical features of BL vary by both EBV status and geographical region, reflecting underlying epidemiological differences. The cell of origin may also differ between EBV-positive and EBV-negative cases. At a molecular level, differences based on EBV status include variations in the immunoglobulin (IG)::MYC translocation breakpoints, mutations in the inhibitor of DNA binding 3 (ID3)/ transcription factor 3 (TCF3)/ cyclin D3 (CCND3) signalling axis, the anti-apoptotic effects of EBV latency gene products, differences in the alternative reading frame (ARF)/ mouse double minute 2 (MDM2)/p53 and ataxia-telangiectasia mutated (ATM)/ ATM and RAD3-related (ATR) pathways, and deregulation of B-cell leukemia/lymphoma 2 (BCL-2) family proteins. We further discuss the theory that aberrant activation-induced cytidine deaminase (AID) expression, in the setting of EBV infection and chronic malaria exposure, is the most likely aetiology of endemic BL.
This review provides a comprehensive summary of key molecular differences between EBV-positive and EBV-negative BL, that may guide the development of future targeted therapeutic strategies.
{"title":"Clinical and molecular variations in Burkitt lymphoma","authors":"Eoghan O’Connor , Patricia Scanlan , Owen Patrick Smith , Melinda Halasz","doi":"10.1016/j.tranon.2025.102611","DOIUrl":"10.1016/j.tranon.2025.102611","url":null,"abstract":"<div><div>Burkitt lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma, historically classified into three subtypes; endemic, sporadic and immunodeficiency associated BL. Accumulating evidence suggests that Epstein-Barr virus (EBV)-positive and EBV-negative BL represent biologically distinct entities. In this review, we aim to compare the clinicopathological and molecular differences in BL in the context of EBV status and chronic malaria infection.</div><div>From our review, clinical features of BL vary by both EBV status and geographical region, reflecting underlying epidemiological differences. The cell of origin may also differ between EBV-positive and EBV-negative cases. At a molecular level, differences based on EBV status include variations in the immunoglobulin (<em>IG</em>)::<em>MYC</em> translocation breakpoints, mutations in the inhibitor of DNA binding 3 (<em>ID3</em>)/ transcription factor 3 (<em>TCF3</em>)/ cyclin D3 (<em>CCND3</em>) signalling axis, the anti-apoptotic effects of EBV latency gene products, differences in the alternative reading frame (ARF)/ mouse double minute 2 (MDM2)/p53 and ataxia-telangiectasia mutated (ATM)/ ATM and RAD3-related (ATR) pathways, and deregulation of B-cell leukemia/lymphoma 2 (BCL-2) family proteins. We further discuss the theory that aberrant activation-induced cytidine deaminase (AID) expression, in the setting of EBV infection and chronic malaria exposure, is the most likely aetiology of endemic BL.</div><div>This review provides a comprehensive summary of key molecular differences between EBV-positive and EBV-negative BL, that may guide the development of future targeted therapeutic strategies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102611"},"PeriodicalIF":5.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623612","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 : 2025-11-24DOI: 10.1016/j.tranon.2025.102617
Rui Wang , Bin Wang , Juanhong Shi , Zhi Zhu , ZhenZhen Yao
There is an urgent need to identify novel therapeutic targets for papillary thyroid carcinoma (PTC). APOC1 (Apolipoprotein C1) has emerged as a candidate: it is overexpressed in several cancers and its high expression often associates with worse clinical outcomes. Using bioinformatic analysis of TCGA-THCA RNA-seq data, we found that APOC1 is highly expressed in PTC and that elevated APOC1 correlates with poorer patient prognosis and with signatures of immune-evasion. We validated these observations in PTC cell lines. Immunofluorescence, colony-formation assays, CCK-8 proliferation measurements, and flow-cytometry apoptosis analysis all indicate that APOC1 promotes proliferation, enhances colony survival, and confers resistance to apoptosis. To identify candidate therapeutics that target APOC1-related pathways, we queried the Connectivity Map using shared differentially expressed genes (DEGs) and nominated cyclopamine as the top small-molecule hit. Cyclopamine reduces PTC cell proliferation and induces apoptosis in vitro; APOC1 depletion further sensitizes cells to cyclopamine, producing greater inhibition of proliferation and increased cell death. Finally, cyclopamine suppresses tumor growth in a PTC mouse model. Together, these results implicate APOC1 as a driver of PTC progression and immune evasion and identify cyclopamine as a promising therapeutic that acts, at least in part, through APOC1-related signaling. Our study thus provides a rationale for targeting APOC1 as a novel treatment strategy for papillary thyroid carcinoma.
{"title":"Apolipoprotein C1 functions as a target of thyroid carcinoma and synergistic effects with promising candidate-cyclopamine","authors":"Rui Wang , Bin Wang , Juanhong Shi , Zhi Zhu , ZhenZhen Yao","doi":"10.1016/j.tranon.2025.102617","DOIUrl":"10.1016/j.tranon.2025.102617","url":null,"abstract":"<div><div>There is an urgent need to identify novel therapeutic targets for papillary thyroid carcinoma (PTC). <em>APOC1</em> (Apolipoprotein C1) has emerged as a candidate: it is overexpressed in several cancers and its high expression often associates with worse clinical outcomes. Using bioinformatic analysis of TCGA-THCA RNA-seq data, we found that <em>APOC1</em> is highly expressed in PTC and that elevated <em>APOC1</em> correlates with poorer patient prognosis and with signatures of immune-evasion. We validated these observations in PTC cell lines. Immunofluorescence, colony-formation assays, CCK-8 proliferation measurements, and flow-cytometry apoptosis analysis all indicate that <em>APOC1</em> promotes proliferation, enhances colony survival, and confers resistance to apoptosis. To identify candidate therapeutics that target <em>APOC1</em>-related pathways, we queried the Connectivity Map using shared differentially expressed genes (DEGs) and nominated cyclopamine as the top small-molecule hit. Cyclopamine reduces PTC cell proliferation and induces apoptosis in vitro; <em>APOC1</em> depletion further sensitizes cells to cyclopamine, producing greater inhibition of proliferation and increased cell death. Finally, cyclopamine suppresses tumor growth in a PTC mouse model. Together, these results implicate <em>APOC1</em> as a driver of PTC progression and immune evasion and identify cyclopamine as a promising therapeutic that acts, at least in part, through <em>APOC1</em>-related signaling. Our study thus provides a rationale for targeting APOC1 as a novel treatment strategy for papillary thyroid carcinoma.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102617"},"PeriodicalIF":5.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145606228","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 : 2025-11-24DOI: 10.1016/j.tranon.2025.102603
Alexandra E. Herzog , Shirley Zheng , Kristy A. Warner , Jaqueline V. Vanini , Ritu Somayaji , Madelynn R. Johnson , Zhaocheng Zhang , Peter J. Polverini , Rogério M Castilho , Alexander T. Pearson , Jacques E. Nör
Cancer stem cells (CSC) drive therapeutic resistance and recurrence in head and neck squamous cell carcinoma (HNSCC). We and others have shown that treatment with cytotoxic chemotherapy agents (e.g. Cisplatin, Carboplatin) induce Bmi-1 expression and increase the fraction of highly tumorigenic CSC in HNSCC. Notably, Bmi-1 is a master regulator of stem cell self-renewal and DNA repair. The purpose of this work was to test whether therapeutic inhibition of Bmi-1 sensitizes HNSCC cancer stem cells to chemotherapy. HNSCC cells (UM-SCC-1,-22A,-22B) were treated with Cisplatin or Carboplatin and subjected to stemness analyses to evaluate the impact of Bmi-1 on chemoresistance. We observed that both, shRNA-mediated Bmi-1 silencing or pharmacologic inhibition of Bmi-1 with the small molecule inhibitor PTC596, blocked chemotherapy-induced cancer stemness (i.e. increase in the fraction of ALDHhighCD44high cells), CSC self-renewal (i.e. orosphere formation) and inhibited protective DNA damage responses in HNSCC. Further, it is known that high IL-6 serum levels correlate with poor HNSCC patient survival, and that platinum-based therapies induce IL-6 signaling. Here, we observed that Bmi-1 silencing (or PTC596 treatment) inhibited the IL-6R/STAT3 signaling pathway even in presence of platinum-based cytotoxic agents (i.e. Cisplatin, Carboplatin). In vivo, Bmi-1 inhibition with PTC596 suppressed Cisplatin-mediated increase in the fraction of ALDHhighCD44high cells (cancer stemness). Collectively, these preclinical results demonstrate that Bmi-1 is a key mediator of head and neck cancer stemness and suggest that HNSCC patients might benefit from treatment with a Bmi-1 inhibitor combined with a conventional chemotherapeutic agent.
{"title":"Bmi-1 inhibition sensitizes head and neck cancer stem cells to cytotoxic chemotherapy","authors":"Alexandra E. Herzog , Shirley Zheng , Kristy A. Warner , Jaqueline V. Vanini , Ritu Somayaji , Madelynn R. Johnson , Zhaocheng Zhang , Peter J. Polverini , Rogério M Castilho , Alexander T. Pearson , Jacques E. Nör","doi":"10.1016/j.tranon.2025.102603","DOIUrl":"10.1016/j.tranon.2025.102603","url":null,"abstract":"<div><div>Cancer stem cells (CSC) drive therapeutic resistance and recurrence in head and neck squamous cell carcinoma (HNSCC). We and others have shown that treatment with cytotoxic chemotherapy agents (<em>e.g.</em> Cisplatin, Carboplatin) induce Bmi-1 expression and increase the fraction of highly tumorigenic CSC in HNSCC. Notably, Bmi-1 is a master regulator of stem cell self-renewal and DNA repair. The purpose of this work was to test whether therapeutic inhibition of Bmi-1 sensitizes HNSCC cancer stem cells to chemotherapy. HNSCC cells (UM-SCC-1,-22A,-22B) were treated with Cisplatin or Carboplatin and subjected to stemness analyses to evaluate the impact of Bmi-1 on chemoresistance. We observed that both, shRNA-mediated Bmi-1 silencing or pharmacologic inhibition of Bmi-1 with the small molecule inhibitor PTC596, blocked chemotherapy-induced cancer stemness (<em>i.e.</em> increase in the fraction of ALDH<sup>high</sup>CD44<sup>high</sup> cells), CSC self-renewal (<em>i.e.</em> orosphere formation) and inhibited protective DNA damage responses in HNSCC. Further, it is known that high IL-6 serum levels correlate with poor HNSCC patient survival, and that platinum-based therapies induce IL-6 signaling. Here, we observed that Bmi-1 silencing (or PTC596 treatment) inhibited the IL-6R/STAT3 signaling pathway even in presence of platinum-based cytotoxic agents (<em>i.e.</em> Cisplatin, Carboplatin). <em>In vivo</em>, Bmi-1 inhibition with PTC596 suppressed Cisplatin-mediated increase in the fraction of ALDH<sup>high</sup>CD44<sup>high</sup> cells (cancer stemness). Collectively, these preclinical results demonstrate that Bmi-1 is a key mediator of head and neck cancer stemness and suggest that HNSCC patients might benefit from treatment with a Bmi-1 inhibitor combined with a conventional chemotherapeutic agent.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102603"},"PeriodicalIF":5.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145606168","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 : 2025-11-23DOI: 10.1016/j.tranon.2025.102610
Aiwen Yan , Zihan Huang , Liang Kong , Zhaoyan Cheng , Yuewen Song , Xiaomao Li , Pan Jiang , Yuhui Yan
Objective: To investigate whether β-Sitosterol (SIT) enhanced the anticarcinogenic effects of sorafenib on HCC. Methods: The anti-tumor effects in vitro were detected using a Cell Counting Kit-8 assay, 5-ethynyl-29-deoxyuridine assay, flow cytometry, wound healing assay and tube formation assay. Blood samples were collected for in vivo biochemical and metabolomic analyses. Anticarcinogenic activity was evaluated by Masson’s trichrome staining in conjunction with hematoxylin and eosin staining. Bioinformatics analyses were conducted to investigate the potential associations between lipid metabolism and HCC. Finally, the lipid- related protein expression was detected by immunohistochemical staining (IHC) and western blot (WB) analysis. Results: In vitro studies demonstrated that the combination of SIT and sorafenib promoted apoptosis and inhibited the growth, proliferation, migration and vasculogenic mimicry formation and of HCC cells. Additionally, the anti-hepatocarcinoma activity of the combination treatment was better than that of sorafenib treatment alone to inhibit diethylnitrosamine-induced HCC progression. Metabolomic, bioinformatics, IHC and WB analyses suggest that SIT regulates lipid metabolism by modulating the expression of FXR, LXR, SREBP1, and FASN. Conclusions: The data suggest that SIT enhances the effect of sorafenib by regulating lipid metabolism targeting FXR, LXR, SREBP1, and FASN, indicating that the strategies to union potent drugs regulating lipid metabolism with sorafenib deserves to be further explored.
{"title":"β-Sitosterol enhances the anti-tumor efficacy of sorafenib in hepatocellular carcinoma via the FXR/LXR/ SREBP1/ FASN pathway","authors":"Aiwen Yan , Zihan Huang , Liang Kong , Zhaoyan Cheng , Yuewen Song , Xiaomao Li , Pan Jiang , Yuhui Yan","doi":"10.1016/j.tranon.2025.102610","DOIUrl":"10.1016/j.tranon.2025.102610","url":null,"abstract":"<div><div><em>Objective:</em> To investigate whether β-Sitosterol (SIT) enhanced the anticarcinogenic effects of sorafenib on HCC. <em>Methods:</em> The anti-tumor effects in vitro were detected using a Cell Counting Kit-8 assay, 5-ethynyl-29-deoxyuridine assay, flow cytometry, wound healing assay and tube formation assay. Blood samples were collected for in vivo biochemical and metabolomic analyses. Anticarcinogenic activity was evaluated by Masson’s trichrome staining in conjunction with hematoxylin and eosin staining. Bioinformatics analyses were conducted to investigate the potential associations between lipid metabolism and HCC. Finally, the lipid- related protein expression was detected by immunohistochemical staining (IHC) and western blot (WB) analysis. <em>Results:</em> In vitro studies demonstrated that the combination of SIT and sorafenib promoted apoptosis and inhibited the growth, proliferation, migration and vasculogenic mimicry formation and of HCC cells. Additionally, the anti-hepatocarcinoma activity of the combination treatment was better than that of sorafenib treatment alone to inhibit diethylnitrosamine-induced HCC progression. Metabolomic, bioinformatics, IHC and WB analyses suggest that SIT regulates lipid metabolism by modulating the expression of FXR, LXR, SREBP1, and FASN. <em>Conclusions:</em> The data suggest that SIT enhances the effect of sorafenib by regulating lipid metabolism targeting FXR, LXR, SREBP1, and FASN, indicating that the strategies to union potent drugs regulating lipid metabolism with sorafenib deserves to be further explored.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"63 ","pages":"Article 102610"},"PeriodicalIF":5.0,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597595","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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