Translational Oncology[JOURNAL]
Sun
200 papers
Unmasking FCGR2B as a high-grade serous ovarian cancer specific marker of immune suppression and tumor progression through multi-omics mining.
Zhou J, Zeng T, Ye M … +5 more , Li M, Wen L, Liu X, Zhang Z, Meng Y
Transl Oncol · 2026 May · PMID 41934917 · Full text
BACKGROUND: Epithelial ovarian cancer (EOC) encompasses five major histological subtypes with marked genetic, immunological, and clinical heterogeneity. While genome-wide association studies (GWAS) have identified subtyp...
BACKGROUND: Epithelial ovarian cancer (EOC) encompasses five major histological subtypes with marked genetic, immunological, and clinical heterogeneity. While genome-wide association studies (GWAS) have identified subtype-specific risk loci, a critical gap remains in understanding how plasma proteins influence immune-cell traits and contribute to EOC pathogenesis. METHODS: We integrated subtype-stratified GWAS data from two EOC cohorts with plasma proteomics and immune-cell traits to construct protein-immune-EOC regulatory landscapes using a three-stage Mendelian randomization framework. Single-cell RNA-seq and multiplex immunofluorescence were employed to delineate the cellular distribution and spatial context of causal proteins. Subsequent analyses characterized immune infiltration, macrophage polarization, and clinicopathological associations. Drug-gene correlations were used to identify potential therapeutic targets, and transcriptomic analyses were applied to delineate the underlying transcriptional landscape. RESULTS: We identified 20 subtype-specific protein-immune-EOC regulatory axes, with FCGR2B emerging as a causal plasma protein in immune regulation and high-grade serous ovarian cancer (HGSOC) progression. FCGR2B was highly expressed in tumor-associated macrophages and was associated with an M2-like polarization phenotype. Functional characterization revealed that FCGR2B was associated with shorter progression-free survival and an immunosuppressive tumor microenvironment. Transcriptomic analyses revealed altered NF-κB signaling upon FCGR2B knockdown, and drug-response data suggested a potential association between high FCGR2B expression and sensitivity to NF-κB inhibitors. CONCLUSIONS: These findings delineate subtype-specific genetically informed protein-immune regulatory landscapes in EOC and identify FCGR2B as a key immunoregulatory and prognostic biomarker in HGSOC, suggesting FCGR2B as a potential therapeutic vulnerability that warrants further investigation.
Synergistic effects through targeting the PI3K and IGFR pathways in treating lung cancer carrying activation alterations along the PI3K pathway.
Abd El-Salam M, Chen W, Tang Y … +9 more , Rao T, Kang X, Sun L, Han T, Chen P, Mossanen M, Cheng F, Yang C, Pan CX
Transl Oncol · 2026 May · PMID 41934916 · Full text
PURPOSE: Alterations in the PI3K/AKT pathway occur in over 60 % of lung squamous cell carcinoma and approximately 20 % of lung adenocarcinoma, driving tumor progression and therapeutic resistance. While PI3K-targeted the...
PURPOSE: Alterations in the PI3K/AKT pathway occur in over 60 % of lung squamous cell carcinoma and approximately 20 % of lung adenocarcinoma, driving tumor progression and therapeutic resistance. While PI3K-targeted therapies suppress proliferation in PIK3CA-mutant non-small cell lung cancer (NSCLC), their clinical impact is limited due to compensatory activation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling. This study aimed to determine whether dual blockade of PI3K and IR/IGF-1R signaling could overcome this adaptive resistance. METHODS: We assessed the effects of combining ceritinib, an ALK and IR/IGF-1R inhibitor, with a PI3K/AKT inhibitor in PIK3CA E545K-mutant H460 NSCLC cells. Functional assays included colony formation, wound healing, Matrigel invasion, and Western blot analyses. Therapeutic efficacy was further evaluated in a patient-derived xenograft (PDX) model of lung squamous cell carcinoma harboring the PIK3CA E545K mutation. Transcriptomic profiling using RNA-seq was conducted to identify resistance-associated pathways, and key findings were validated by qRT-PCR. RESULTS: Genetic ablation of PIK3CA markedly reduced proliferation. Dual inhibition of PI3K and IR/IGF-1R signaling resulted in strong synergistic anti-proliferative, anti-migratory, and anti-invasive effects in vitro. In the PDX model, the combination therapy significantly prolonged overall survival without additional systemic toxicity. Transcriptomic analysis revealed activation of the TNF-α/NF-κB axis as a potential mechanism of acquired resistance. CONCLUSION: Concurrent targeting of PI3K and IR/IGF-1R signaling effectively overcomes adaptive resistance in PIK3CA-mutant NSCLC, supporting the rationale for further clinical evaluation of this combined therapeutic strategy.
Pan-cancer analysis identifies FKBP10 as a regulator of tumor immunosuppression and therapeutic response.
Li Y, Chen J, Li S … +2 more , Tu G, Tang L
Transl Oncol · 2026 May · PMID 41934915 · Full text
BACKGROUND: Tumor immune regulation depends on interactions between intrinsic molecular mechanisms, tumor cell metabolic states, and the immune microenvironment. The ER‑localized isomerase FK506‑binding protein 10 (FKBP1...
BACKGROUND: Tumor immune regulation depends on interactions between intrinsic molecular mechanisms, tumor cell metabolic states, and the immune microenvironment. The ER‑localized isomerase FK506‑binding protein 10 (FKBP10) is essential for extracellular matrix homeostasis, but its systemic role in cancer immune regulation and therapeutic response remains unclear. METHODS: A pan‑cancer analysis of 33 TCGA tumor types integrated copy number variation, DNA methylation, and mutation data to elucidate FKBP10 regulation. ESTIMATE, ImmuCellAI, and TIMER2 assessed immune infiltration and immunosuppressive phenotypes, and pathway enrichment identified FKBP10‑related metabolic reprogramming, ECM remodeling, EMT, and programmed cell death signals. Therapeutic response was evaluated using breast cancer in vitro assays and GDSC drug sensitivity data. RESULTS: FKBP10 was significantly upregulated in multiple cancers, especially breast and renal carcinoma, and strongly associated with poor prognosis. Its high expression was mainly driven by promoter hypomethylation and copy number amplification. FKBP10‑high tumors showed enhanced ECM remodeling, metabolic reprogramming, and apoptosis resistance, accompanied by an immunosuppressive microenvironment with reduced cytotoxic T cells and enrichment of myeloid‑derived suppressor cells and cancer‑associated fibroblasts. High FKBP10 expression also correlated with decreased sensitivity to several chemotherapeutic agents. In vitro experiments confirmed that FKBP10 promotes tumor cell proliferation and clonogenicity. CONCLUSIONS: FKBP10 is closely linked to tumor progression and treatment response by contributing to metabolic reprogramming, immunosuppressive microenvironment modulation, and programmed cell death regulation, supporting its potential as a biomarker and therapeutic target for predicting prognosis, treatment response, and immunotherapy outcomes.
Statins targeting mevalonate-geranylgeranyl diphosphate pathway inhibit proliferation in NK/T lymphoma by promoting pyroptosis.
Wang Y, Mei M, Wang J … +3 more , Wei L, Zhang M, Zhang M
Transl Oncol · 2026 May · PMID 41932011 · Full text
Pyroptosis, an inflammation-driven programmed cell death, plays a pivotal role in the carcinogenicity of various tumors. Given the proven antitumor effects of statins, this study investigated whether statins suppress nat...
Pyroptosis, an inflammation-driven programmed cell death, plays a pivotal role in the carcinogenicity of various tumors. Given the proven antitumor effects of statins, this study investigated whether statins suppress natural killer /T cell lymphoma (NKTCL) via pyroptosis and the underlying mechanism. NKYS and YT cells were treated with different concentrations of statins. The carcinogenicity of cells was validated through cell viability and invasion assays. The level of cell cycle, apoptosis, and the number of pyroptosis cells were evaluated via flow cytometry. Western-blot and immunofluorescence assays were conducted to verify the expressions of pyroptosis and immunity related proteins. The morphological characteristics of cell pyroptosis were observed via transmission electron microscopy. A subcutaneous transplant tumor model was used to verify the inhibitory effect of fluvastatin (FLU) on NKTCL cells in vivo. FLU inhibited the carcinogenicity of NKTCL cells in a concentration-dependent manner, and activated pyroptosis and its related immunity levels, which were represented by swelling of cell morphology, formation of inflammasome, and elevated expressions of gasdermin D, cleaved caspase-1 and interleukin-1β/18. Administration of pyroptosis inhibitors and exogenous mevalonate (MVA) or geranyl pyrophosphate (GGPP) partially weakened the inhibitory effect of FLU on NKTCL cells both in vitro and in vivo. Lastly, FLU and gemcitabine demonstrated satisfactory synergistic effects in tumor suppression and pyroptosis activation. Our data suggest that FLU represses NKTCL growth by promoting pyroptosis via the MVA-GGPP pathway.
EGR1 lactylation induces tumor cell senescence and immunosuppressive microenvironment in intrahepatic cholangiocarcinoma.
Liang Y, Zhang R, Li Y … +12 more , Wang H, Qiao L, Bu Q, Xu Z, Liu Z, Song Z, Huang T, Liu M, Zhou J, Wang Q, Chen Q, Lu L
Transl Oncol · 2026 May · PMID 41932010 · Full text
BACKGROUND: Cellular senescence, which is a hallmark of cancer, has been gaining increasing attention in recent years. However, its role in immunosuppressive microenvironment of intrahepatic cholangiocarcinoma (iCCA) rem...
BACKGROUND: Cellular senescence, which is a hallmark of cancer, has been gaining increasing attention in recent years. However, its role in immunosuppressive microenvironment of intrahepatic cholangiocarcinoma (iCCA) remains poorly understood. METHODS: We utilized publicly available bulk and single-cell transcriptomic datasets of iCCA to identify senescent tumor cells and the cell type composition within the immunosuppressive microenvironment. Then, the roles of senescent tumor cells and immunosuppressive cell types were verified through in vitro and in vivo experiments. RESULTS: We defined a 101 iCCA senescence-related gene signature (ISG) to assess cellular senescence in iCCA. Higher ISG levels indicate a poorer prognosis and increased infiltration of immunosuppressive cell types. We observed that the ISG-high malignant subgroup exhibits low proliferation but high stemness. Meanwhile, the ISG-high malignant cells upregulated the hypoxia and glycolysis pathways. Furthermore, we identified the key transcriptional factor EGR1 and demonstrated its regulatory role in the expression of CDKN1A. Mechanistically, the K422 site of EGR1 undergoes lactylation, which promotes its nuclear translocation and further regulates the transcription of CDKN1A, ultimately leading to the induction of the senescence phenotype. Moreover, cell-cell interaction analysis revealed that ISG-high malignant cells recruited and regulated immunosuppressive MACRO tumor-associated macrophages through the LGALS9-CD44/THBS1-CD47 axis, and the immunosuppressive MACRO TAMs could also recruit Tregs through the CXCL12-CXCR4 axis, thereby forming an immunosuppressive microenvironment. CONCLUSION: We defined a novel ISG signature in iCCA and identified EGR1 as a critical driver of senescent tumor cells in iCCA.These findings offer new insights into senescent tumor cells and the immunosuppressive microenvironment.
Small but mighty: Peptides as next-generation immunotargeting agents in gynecological cancers.
Garg P, Krishna M, Singhal SS
Transl Oncol · 2026 May · PMID 41930712 · Full text
The most common cancers in women, ovarian, cervical and endometrial, are still a significant cause of cancer-related illness and death around the world. Success with the newest immunotherapy can only be achieved when the...
The most common cancers in women, ovarian, cervical and endometrial, are still a significant cause of cancer-related illness and death around the world. Success with the newest immunotherapy can only be achieved when the treatment targets the tumor accurately. Although monoclonal antibodies, aptamers and antisense oligonucleotides are traditionally used in immunotargeting, they face challenges related to bulkiness, their price, immune response and reaching tumors. For these reasons, peptides are now considered important next-generation substances for immunotargeting. This review describes how peptides are becoming increasingly significant in gynecological oncology through their application in drug targeting, imaging cancer, and making vaccines. Findings on how peptide targeting systems measure up to other approaches and some recent advances in designing peptide-drug conjugates, receptor-targeting therapies, and CAR-T therapies are discussed. This review also discuss about how peptides are stable, how to deliver them selectively and how artificial intelligence supports better peptide designing. With the development of precision medicine, the use of peptide-based immunotargeting can greatly improve both the success and safety of treatments for cancer of the uterus and ovaries.
Supersensitive and robust disease monitoring in oropharyngeal cancer patients by circulating tumor HPV-DNA sequencing (ctHPV-DNAseq).
Pierik AS, Poell JB, Brink A … +14 more , Stigter-van Walsum M, Jansen F, de Bree R, Hardillo J, Langendijk JA, Takes RP, Lamers F, Verdonck-de Leeuw IM, Hendrickx JJ, Koppes SA, Rosing F, Waterboer T, Leemans CR, Brakenhoff RH
Transl Oncol · 2026 May · PMID 41921264 · Full text
BACKGROUND: Post-treatment disease monitoring of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is challenging. Liquid biopsies could improve disease monitoring, but the variety in methods hampers clinical im...
BACKGROUND: Post-treatment disease monitoring of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is challenging. Liquid biopsies could improve disease monitoring, but the variety in methods hampers clinical implementation. In this study, target-enrichment sequencing to detect circulating tumor HPV DNA (ctHPV-DNA) was applied in liquid biopsies of HPV-positive OPSCC patients, and robust statistical readouts determined. Next, it was investigated whether longitudinal plasma monitoring could accurately diagnose residual and recurrent disease. METHODS: The target-enrichment panel included 29 cancer genes and high-risk HPV genomes. The assay was tested on plasma from 30 non-cancer controls and 33 patients with HPV-positive tumors, 15 of whom had residual or recurrent disease, and 18 who remained disease-free. Samples were analyzed from baseline to 24 months after treatment. RESULTS: By determining and applying robust statistical cut-off values, ctHPV-DNA could be detected in plasma of all patients with HPV-positive OPSCC at baseline, and was absent in plasma of all non-cancer controls. In OPSCC patients who remained disease-free, post-treatment plasma samples were negative for ctHPV-DNA. In contrast, ctHPV-DNA was detected in plasma of all OPSCC patients with recurrent disease to a year before clinical diagnosis. Cases suspect for residual disease in the neck, but with a necrotic metastasis without vital tumor after resection, tested correctly negative for ctHPV-DNA in plasma. CONCLUSIONS: Target-enrichment sequencing of plasma shows 100% accurate detection of ctHPV-DNA at baseline. Longitudinal monitoring enables early recurrence detection and correct diagnosis of non-vital residual disease. The data indicate that liquid biopsy could improve post-treatment follow-up in HPV-positive OPSCC patients.
Machine learning derived ORC6 as a hub biomarker for predicting tumor microenvironment, prognoses, and therapeutic responses in lung adenocarcinoma.
Huang X, Feng D, Tian Y … +4 more , Zhang X, Li Y, He Y, Liu Y
Transl Oncol · 2026 May · PMID 41875810 · Full text
The origin recognition complex (ORC) is a DNA-binding complex composed of six subunits involved in DNA replication in cancer cells. The prognostic and immunological implications of ORC6 in lung adenocarcinoma (LUAD) are...
The origin recognition complex (ORC) is a DNA-binding complex composed of six subunits involved in DNA replication in cancer cells. The prognostic and immunological implications of ORC6 in lung adenocarcinoma (LUAD) are not yet clear. This study utilizes multiple databases (such as TCGA, GEO, GTEx, etc.) to investigate the potential significance of ORC6 in LUAD. The results show that high ORC6 expression is associated with advanced disease and poorer prognosis and is involved in biological processes such as cell cycle regulation, DNA replication, and signal transduction. The expression of ORC6 correlates negatively with the infiltration of CD4+ and CD8+ T cells but positively with the infiltration of cancer-associated fibroblasts and endothelial cells. Additionally, a positive correlation between ORC6 and immunosuppression-related genes (such as LAG3 and PDCD1) was found. Validation of ORC6 expression was conducted through qRT-PCR, western blotting, and immunofluorescence, indicating its potential diagnostic, prognostic, and therapeutic value in LUAD.
SNHG7 interacts with PCBP2 to promote CDKN2A expression and modulate cuproptosis in colorectal cancer.
Chen Q, Song Q, Zhang H … +11 more , Lin Z, Shi Y, Chai Y, Fang X, Li N, Zheng Y, Yang Y, Wu X, Wang S, He C, Li M
Transl Oncol · 2026 May · PMID 41875809 · Full text
Colorectal cancer (CRC) ranks as the third most common malignancy worldwide. Cyclin dependent kinase inhibitor 2A (CDKN2A) is a key regulatory gene in the recently identified cell death pathway known as cuproptosis. The...
Colorectal cancer (CRC) ranks as the third most common malignancy worldwide. Cyclin dependent kinase inhibitor 2A (CDKN2A) is a key regulatory gene in the recently identified cell death pathway known as cuproptosis. The small nucleolar RNA host gene 7 (SNHG7) is an important and versatile molecule engaged in a variety of tumorigenic processes. Poly(rC)-binding protein 2 (PCBP2) is an RNA-binding protein that enhances RNA stability and is implicated in the progression of various tumors. However, the clinical role of cuproptosis-related SNHG7 in CRC largely remains unclear. We conducted cell culture and subcutaneous tumor formation experiments in nude mice, followed by qPCR, Western blotting, RNA immunoprecipitation, lactate production assays, gel electrophoresis, and immunohistochemistry on the corresponding tissues. Our results demonstrate that SNHG7 interacts with PCBP2 to enhance the expression of CDKN2A, thereby modulating cuproptosis and promoting glycolysis. These findings suggest that SNHG7 represents a promising therapeutic target for CRC.
Integrated single-cell and bulk transcriptomics reveals STAB1 as a novel therapeutic target for ovarian cancer.
Zhang Y, Chen J, Tang L … +3 more , Sun X, Yang L, Zhong Z
Transl Oncol · 2026 May · PMID 41865597 · Full text
The immunosuppressive tumor microenvironment (TME) and intrinsic heterogeneity of ovarian cancer (OC) are primary drivers of therapeutic resistance and mortality. To deconvolute these complex dynamics and identify robust...
The immunosuppressive tumor microenvironment (TME) and intrinsic heterogeneity of ovarian cancer (OC) are primary drivers of therapeutic resistance and mortality. To deconvolute these complex dynamics and identify robust therapeutic targets, this study employed an integrative strategy combining ensemble machine learning algorithms with high-resolution single-cell transcriptomics and experimental validation. Through dual-feature selection (LASSO and SVM-RFE) applied to multi-cohort bulk transcriptomic data, we identified Stabilin-1 (STAB1) as a top-ranked prognostic determinant. Crucially, single-cell analysis of the OC ecosystem redefined the cellular localization of STAB1, revealing its predominant enrichment in LYVE1+ perivascular-like M2 macrophages and a hyper-aggressive, EMT-active tumor subpopulation. Validating these in silico insights, in vitro loss-of-function assays confirmed that STAB1 silencing in OC cell lines (A2780 and SK-OV-3) significantly suppressed cell proliferation, colony formation, and invasion. Collectively, our findings support STAB1 as a pivotal "dual-checkpoint" molecule that bridges the immunosuppressive stroma and the malignant epithelium, highlighting its potential as a novel therapeutic target for dismantling the ovarian cancer ecosystem.
THOC3 interacts with epithelial-to-mesenchymal transition to promote non-small cell lung cancer carcinoma progression through STAT3 signaling pathway.
Ni Z, Zhou S, Zhang Y … +4 more , Wang X, Yang H, Zhou H, Tao Z
Transl Oncol · 2026 May · PMID 41865596 · Full text
Located on chromosome 5, the THOC3 gene encodes a protein of 351 amino acids, though its precise biological role in various malignancies, including lung cancer (LC), remains to be fully clarified. Elevated expression of...
Located on chromosome 5, the THOC3 gene encodes a protein of 351 amino acids, though its precise biological role in various malignancies, including lung cancer (LC), remains to be fully clarified. Elevated expression of THOC3 was observed in LC (IHC) analyses. Increased THOC3 levels were associated with advanced tumor stages and poorer prognosis in patients. Functional studies using both loss-of-function and gain-of-function approaches suggested that THOC3 may influence cellular proliferation, tumorigenic potential, and apoptosis in vitro. Mechanistically, its effects appear to involve activation of the STAT3 pathway. Additionally, Garcinone d-induced STAT3 activation mitigated certain malignant characteristics of LC cells, though silencing THOC3 reversed this effect. These results indicate that THOC3 may serve as a potential prognostic marker and could warrant further investigation as a therapeutic target in LC.
The brain imaging feature-related gene NRP2 drives the malignant progression of glioblastoma through the FAK pathway: a Mendelian randomization study.
Li Y, Que J, Xia Y … +4 more , Wang L, Zhang P, Cheng Z, Gao B
Transl Oncol · 2026 May · PMID 41861662 · Full text
BACKGROUND: Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. Although brain imaging features are related to biological behaviors of GBM, the causal relationship between them remain unclear. OB...
BACKGROUND: Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. Although brain imaging features are related to biological behaviors of GBM, the causal relationship between them remain unclear. OBJECTIVES: To explore the causal relationship between brain imaging features and GBM, identify key pathogenic genes, and provide a perspective for GBM therapy. METHODS: Two-sample MR analysis was employed. Causal relationships were evaluated based on brain imaging features, eQTL, and GWAS data. Differentially expressed brain imaging-related genes were screened through gene mapping and differential expression analysis. MR analysis on eQTL data identified key genes, and GSEA was performed. Given its robust genetic association, high expression in GBM, and enrichment association with tumor malignancy, NRP2 was determined as the core gene, with its function verified by in vitro/in vivo experiments. RESULTS: MR analysis identified 255 GBM-associated brain imaging features, with 9 key genes selected. NRP2 was identified as a risk gene. NRP2 knockdown significantly inhibited GBM proliferation, migration, and invasion and promoted apoptosis. The inhibitory effects were reversed by activated FAK-signaling pathway. Mechanistically, NRP2 regulated FAK phosphorylation through direct binding, thereby activating the Focal-adhesion pathway and promoting tumor malignancy. In animal experiments, inhibiting NRP2 slowed tumor growth, which was weakened by FAK agonists. CONCLUSION: This study establishes the causal relationship between brain imaging features and GBM from a genetic perspective. NRP2 activates Focal-adhesion pathway through FAK signaling to drive GBM progression. NRP2 is a key molecule connecting imaging phenotypes and GBM malignant behaviors, serving as a potential therapeutic target.
L-type calcium channel-mediated lipid metabolic reprogramming in gastric adenocarcinoma progression.
Cui M, Cheng S, Wen X … +5 more , Yang H, Huang Y, Pan L, Wei S, Huang H
Transl Oncol · 2026 May · PMID 41861661 · Full text
BACKGROUND: l-type calcium channels (LTCCs) play an important role in tumorigenesis, but their expression profile, functional significance, and therapeutic potential in gastric adenocarcinoma (GAC) remain unclear. Concur...
BACKGROUND: l-type calcium channels (LTCCs) play an important role in tumorigenesis, but their expression profile, functional significance, and therapeutic potential in gastric adenocarcinoma (GAC) remain unclear. Concurrently, aberrant lipid metabolism is widely acknowledged as a key driver of GAC progression, but its upstream regulatory mechanisms have yet to be fully elucidated. This study was designed to explore the association between LTCCs and lipid metabolic reprogramming in GAC and to investigate its influence on GAC progression and clinical outcomes. METHODS: The expression profiles of LTCCs family members in GAC were analyzed using the TCGA database. Gastric cancer cells were treated with the LTCCs antagonist (+)-Bay-K-8644, and its effect on the malignant phenotype of the cells was detected by CCK-8, clone formation, scratch healing and transwell assay. Metabolic changes were analyzed by UPLC-Q-TOF-MS metabolomics. The role of lipid metabolism in the regulation of LTCCs was verified by palmitic acid (PA) backfill assay. RESULTS: Bioinformatics analysis showed that Voltage-dependent LTCCs subunit alpha-1D (CACNA1D) was up-regulated in GAC. CACNA1D had excellent diagnostic value and its high expression was associated with poor prognosis. (+)-Bay-K-8644 significantly inhibited gastric cancer cells' proliferation, clone formation, and migration ability. Metabolomics analysis revealed that (+)-Bay-K-8644 treatment resulted in reprogramming of lipid metabolism. Exogenous PA was able to partially reverse the anticancer effects of (+)-Bay-K-8644 and restore cell proliferation and migration. CONCLUSIONS: This study elucidated the unique expression pattern of LTCCs in GAC for the first time, and confirmed that LTCCs antagonism exerts anticancer effects by inducing reprogramming of lipid metabolism. These findings provide a theoretical basis for repositioning calcium channel blockers for GAC therapy and suggest that combined targeting of calcium channels and lipid metabolism may become a new strategy for GAC treatment.
Finely-tuned regulator of DNA repair: FBXW7-185aa may modulate glioblastoma radiosensitization and the tumor immune microenvironment.
Li Z, Hu N, Zhou S … +11 more , Guo X, Yang Z, Jing Z, Li H, Tao Y, Hu W, Liang W, Li J, Lyu Y, Fu X, Wang X
Transl Oncol · 2026 May · PMID 41861660 · Full text
DNA double-strand breaks (DSBs) are among the most severe forms of DNA damage, and their cellular consequences depend on the efficiency of DNA repair pathways. Non-homologous end joining (NHEJ) provides a rapid mechanism...
DNA double-strand breaks (DSBs) are among the most severe forms of DNA damage, and their cellular consequences depend on the efficiency of DNA repair pathways. Non-homologous end joining (NHEJ) provides a rapid mechanism to reconnect broken DNA strands and is a major pathway for maintaining genomic stability. FBXW7α is the substrate-selective unit within the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, imparting specificity by recruiting proteins destined for ubiquitin-mediated turnover. It has recently been reported to mediate XRCC4 ubiquitylation during DNA damage, and is a recognized tumor suppressor, thereby promoting NHEJ. A circular RNA derived from FBXW7 gene exons 3 and 4 (circ-FBXW7) has been identified. This circRNA encodes a 185-amino acid protein, named FBXW7-185aa, which contains a spanning-junction open reading frame (ORF). We found that compared with FBXW7α, FBXW7-185aa was recruited more slowly to DNA damage sites in glioblastoma (GBM) cells. Functionally, FBXW7-185aa may enhance NHEJ repair by facilitating the removal of FBXW7α from DNA damage lesions, thereby promoting the subsequent steps of DNA repair. Efficient DNA repair can enable tumor cells to survive genotoxic stressors like radiotherapy. Radiotherapy is also known to modulate the tumor immune microenvironment. Therefore, our findings suggest that FBXW7-185aa may represent a potential molecular nexus between DNA damage response and tumor-immune interactions. Moreover, depletion of FBXW7-185aa was associated with increased sensitivity of GBM cells to pevonedistat, a drug that inhibits the ubiquitin-like modification of the protein NEDD8, when combined with radiation. Together, our results indicate that FBXW7-185aa acts as a fine-tuning regulator of NHEJ through its interaction with FBXW7α, adding a new layer to the complexity of FBXW7 gene-derived proteins in DNA repair. These findings provide a mechanistic basis for exploring how fine-tuned DNA repair dynamics may influence GBM radiosensitivity and potentially impact tumor immunogenicity, although direct immunological effects remain to be determined.
UCHL1 promotes temozolomide resistance in glioblastoma by inhibiting the ubiquitination-mediated degradation of keratin 8.
Zheng R, Chen X, Xu G … +7 more , Liu Q, Hu S, Shi H, Zhu Z, Ding X, Zhang H, Wang W
Transl Oncol · 2026 May · PMID 41861659 · Full text
BACKGROUND: Resistance to temozolomide (TMZ)-based chemotherapy is a major cause of progression and recurrence in patients with glioblastoma. Although the deubiquitinating enzyme ubiquitin C-terminal hydrolase L1 (UCHL1)...
BACKGROUND: Resistance to temozolomide (TMZ)-based chemotherapy is a major cause of progression and recurrence in patients with glioblastoma. Although the deubiquitinating enzyme ubiquitin C-terminal hydrolase L1 (UCHL1) has been implicated in tumor chemoresistance, its roles and underlying mechanisms in TMZ resistance remain unclear. METHODS: Bioinformatics analyses and immunohistochemistry were used to assess the prognostic significance and the levels of UCHL1 in glioma specimens. Co-immunoprecipitation assays and mass spectrometry were performed to identify protein interactors of UCHL1. The impact of the UCHL1-Keratin 8 (KRT8) axis on TMZ resistance was evaluated using the cell counting kit-8 (CCK-8) assay and western blotting. RESULTS: We found that UCHL1 induced resistance of glioblastoma cells to TMZ. Moreover, UCHL1 expression was significantly upregulated in patients with TMZ-resistant glioma and correlated with poor prognosis. As a deubiquitinase belonging to the UCH enzyme family, UCHL1 utilizes its deubiquitination activity to remove K27-linked polyubiquitin chains from KRT8, thereby preventing KRT8 degradation by the proteasome and maintaining its stability. In vitro assays further demonstrated that depletion of the UCHL1-KRT8 axis weakened chemoresistance by increasing TMZ-induced apoptosis. CONCLUSION: These findings reveal a novel signaling axis underlying TMZ resistance in glioblastoma and highlight the UCHL1-KRT8 axis as a promising therapeutic target.
Exploring survival-associated transcriptomic subtypes in ovarian cancer using RNAseq from FFPE tissues in a clinical trial cohort.
Kjeldsen MK, Bagger FO, Roed H … +18 more , Nyvang GB, Haslund CA, Knudsen AO, Motavaf AK, Malander S, Anttila M, Lindahl G, Mäenpää J, Dimoula M, Werner T, Iversen TZ, Hietanen S, Fokdal L, Dahlstrand H, Bjørge L, Birrer M, Mirza MR, Rossing M
Transl Oncol · 2026 May · PMID 41861658 · Full text
OBJECTIVE: Transcriptomic subtyping is not yet standardized for prognostic use in epithelial ovarian cancer (EOC). This study aims to validate RNA sequencing (RNAseq) from formalin-fixed, paraffin-embedded (FFPE) tissues...
OBJECTIVE: Transcriptomic subtyping is not yet standardized for prognostic use in epithelial ovarian cancer (EOC). This study aims to validate RNA sequencing (RNAseq) from formalin-fixed, paraffin-embedded (FFPE) tissues and to evaluate survival-associated transcriptomic subtypes and differentially expressed genes (DEGs) in a clinical trial cohort. METHODS: An exploratory post hoc analysis was conducted on FFPE samples from patients enrolled in the ENGOT-ov24/NSGO-AVANOVA1&2 trial. RNA was extracted and sequenced, and gene expression analysis was performed to classify subtypes using established, microarray-based, algorithms. Differentially expressed genes (DEGs) were identified based on survival groups, and survival outcomes were analyzed using Kaplan-Meier curves. RESULTS: Of 96 eligible samples, 82 were included in the final analysis. Subtype classifications showed moderate agreement across RNAseq data formats. However, gene expression variability showed inconsistent concordance with clinical metadata and molecular subtypes. Eighteen genes were differentially expressed between long- and short-term survivors. Notably, DPEP3 and SLC14A1, were significantly upregulated in long-term survivors. Despite distinct expression patterns, no significant survival differences were observed between subtypes. CONCLUSIONS: This study demonstrates the feasibility of using RNAseq on FFPE tissue in EOC, while also highlighting challenges of applying microarray-based transcriptomic subtypes to RNAseq data. Transcriptomic analysis identified potential prognostic gene candidates but also highlighted the need to refine classification tools. Further research is essential to improve the molecular classification of EOC, thereby enhancing prognostic accuracy and guiding future therapeutic strategies.
Single-cell inflammatory signaling defines a novel CEP135 endothelial subtype associated with glioma progression.
Ji Z, Kahlert UD, Wu S … +7 more , Dumitru CA, Sandalcioglu E, Zhang J, Wang D, Qu J, Shi W, Yan B
Transl Oncol · 2026 May · PMID 41861657 · Full text
BACKGROUND: Chronic inflammation is a key driver of glioma progression, but its cellular organization within the tumor microenvironment remains poorly understood. METHODS: This study employed an integrated multi-omics an...
BACKGROUND: Chronic inflammation is a key driver of glioma progression, but its cellular organization within the tumor microenvironment remains poorly understood. METHODS: This study employed an integrated multi-omics analysis strategy, combining bulk transcriptomics, proteomics, and glioma cell line expression data with single-cell RNA sequencing data from paired gliomas and adjacent normal brain tissues. Inflammatory signaling activity was quantitatively assessed using pathway-level scoring methods, endothelial cell heterogeneity was analyzed at single-cell resolution, and pseudo-temporal trajectory analysis and cell-cell communication analysis were further conducted. Immunohistochemical analysis was performed using human glioma brain tissue samples from our center to independently validate key findings at the protein level. RESULTS: Bulk transcriptomics analysis revealed significantly activated inflammatory signals in glioblastomas. Single-cell analysis identified a highly inflammatory endothelial cell subtype that was significantly enriched in tumor tissues. Cell communication analysis further revealed enhanced signal output capabilities and participation in neurally-related ligand-receptor interactions. CEP135 was specifically enriched in this endothelial cell subtype and showed consistent upregulation of both transcriptional and protein levels across multiple independent datasets. Immunohistochemical analysis of glioma brain tissue from our center confirmed that CEP135 is primarily localized in tumor-associated endothelial regions, and its expression level was significantly correlated with increasing tumor grade.High CEP135 expression was associated with poor treatment response, shorter survival outcomes. CONCLUSION: This study identified a innovative CEP135+inflammation-associated endothelial cell subtype and established CEP135 as a key biomarker linking endothelial inflammation reprogramming, tumor progression, and adverse clinical outcomes.
Genomic landscape of pleural mesothelioma in Japanese patients: A comprehensive analysis using nationwide database.
Taniguchi H, Akagi K, Fukuda T … +17 more , Honda T, Kurohama H, Ueki N, Matsuoka Y, Udo E, Yahata S, Miura S, Tomono H, Honda N, Dotsu Y, Matsuo M, Takemoto S, Sato I, Okano S, Nakashima M, Mukae H, Ashizawa K
Transl Oncol · 2026 May · PMID 41855858 · Full text
Pleural mesothelioma (PM) is a rare and aggressive malignancy. The development of novel therapeutic strategies targeting PM remains an unmet clinical need. However, comprehensive genomic data from Asian populations, part...
Pleural mesothelioma (PM) is a rare and aggressive malignancy. The development of novel therapeutic strategies targeting PM remains an unmet clinical need. However, comprehensive genomic data from Asian populations, particularly from Japanese patients, are limited. This study aimed to elucidate the genomic landscape of PM in Japanese patients using the nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) genomic database. A total of 211 patients registered between June 2019 and March 2025 were analyzed. The most frequent genetic alterations were in BAP1, NF2, TP53, CDKN2A/B, and MTAP. The median tumor mutation burden (TMB) was 1.26, and no microsatellite instability-high patients were detected. The median overall survival (OS) after first-line treatment was 30.6 months. Patients treated with immune checkpoint inhibitors (ICIs) had a significantly better OS than those who did not receive ICIs. In univariate and multivariate analyses, TP53 alterations and high TMB (cutoff value of 1.6) were associated with poor prognosis. These results suggest that integrating clinical and genomic data can enhance prognostic stratification and contribute to the development of precision medicine for PM. This study provides the first large-scale genomic characterization of Japanese PM patients with C-CAT and highlights potential biomarkers for future therapeutic development.
Spatial remodeling of the tumor immune microenvironment in hepatocellular carcinoma with cirrhosis driven by Treg-CD8⁺T cell crosstalk via the SPP1-ITGA4 axis.
Xue D, Qiu X, Bao M … +12 more , Song D, Lin Y, Bao J, Wu J, Zhou T, Wang S, Yang S, Hu J, Shen S, Cai J, Wang H, Chen L
Transl Oncol · 2026 May · PMID 41855857 · Full text
OBJECTIVE: The tumor microenvironment (TME) of hepatocellular carcinoma (HCC) is shaped by underlying liver pathology, with potentially distinct features in HCC without cirrhosis (Non-cirrHCC) compared to HCC with cirrho...
OBJECTIVE: The tumor microenvironment (TME) of hepatocellular carcinoma (HCC) is shaped by underlying liver pathology, with potentially distinct features in HCC without cirrhosis (Non-cirrHCC) compared to HCC with cirrhosis (CirrHCC); however, these background-specific differences remain incompletely understood. This study aimed to systematically characterize and compare the cellular composition, spatial organization, and immunoregulatory interactions of the TME between Non-cirrHCC and CirrHCC. METHODS: Total 278 HBV-positive cases and mapped 2,837,999 cells across 11 major cell types were applied for spatial analysis. Subsequently, we integrated the spatial data with publicly available single-cell RNA-seq datasets for downstream analysis. RESULTS: Comparative analysis demonstrated marked differences in immune cell composition between Non-cirrHCC and CirrHCC, with CirrHCC characterized by a pronounced decline in functionally active CD8⁺ T cells. We identified 10 distinct heterotypic cellular neighborhoods (HCNs) representing the heterotypic architecture of the tumor microenvironment. Notably, CirrHCC exhibited an immunosuppressive microenvironment with increased spatial proximity between Tregs and CD8T_CD107a⁺ cells, leading to reduced CD8⁺ T cell functional signaling. Integration with single-cell RNA sequencing from public database further indicated that, in CirrHCC, Tregs preferentially interact with the CD8T_CD107a+ cells, potentially mediated by the SPP1-ITGA4 signaling axis. CONCLUSION: In conclusion, CirrHCC promotes a spatially organized Treg-CD8T_CD107a⁺ suppressive niche that constrains CD8⁺ T cell effector function in HCC, with SPP1-ITGA4 emerging as a potential mediating pathway.
Ex vivo organotypic culture of liposarcoma effectively models in vivo supratherapeutic paclitaxel localized drug delivery.
Caturegli I, Liu R, Rivera V … +4 more , Taub O, Grinstaff MW, Colson YL, Raut CP
Transl Oncol · 2026 May · PMID 41855856 · Full text
BACKGROUND: Retroperitoneal sarcomas (RPS) exhibit a high locoregional recurrence rate after macroscopically complete surgical resection. Systemic therapies have limited efficacy and significant adverse effects. Sarcoma...
BACKGROUND: Retroperitoneal sarcomas (RPS) exhibit a high locoregional recurrence rate after macroscopically complete surgical resection. Systemic therapies have limited efficacy and significant adverse effects. Sarcoma cell lines are susceptible to paclitaxel (PTX), a microtubule stabilizer, in 2-dimensional (2-D) monolayer cell culture, but resistant in animal models. When locally delivered via drug-eluting buttresses supratherapeutic concentrations are achieved and PTX becomes efficacious. Due to the limitations of 2-D culture, we establish an organotypic culture system to model the mechanisms by which supratherapeutic and prolonged exposure of PTX is effective. METHODS: Liposarcoma tumors (LP6) were established subcutaneously in NU/J mice. Tumors were harvested, sliced with a vibratome (250 µm thick), and cultured on permeable trans wells. RESULTS: Organotypic culture viability was maintained up to 7 days with greater than 50 % viability. Tumor slices were composed of 82 % ± 7 % human liposarcoma cells with the remainder being mouse stroma as determined by CD44 staining. Under 4-day exposure, IC of PTX with organotypic culture shifted 7000 rightward as compared to 2-D culture. A subset of 17 genes was significantly differentially expressed as compared to untreated controls, while no genes were differentially expressed after 1 day of treatment. Gene set enrichment analysis demonstrated enrichment in apoptotic, extracellular matrix, cell motility, and cell cycle pathways. Caspase-8 activation occurred only at 10,000 ng/mL and 4-days of PTX or greater. CONCLUSION: This study reports a reproducible, clinically relevant organotypic culture liposarcoma model, which can serve as an intermediary between in vitro and in vivo studies.
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