Translational Oncology最新文献

Liver metastasis is the predominant cause of mortality among individuals diagnosed with colorectal cancer (CRC). However, the mechanisms underlying the tumor-microenvironment interactions that promote this process remain poorly defined. Here, we developed an integrative multiomics framework to dissect the cellular and molecular determinants of colorectal cancer liver metastasis (CRLM). By analyzing 1,156 metastasis-associated genes, we identified three molecular subtypes with distinct prognostic and immunometabolic features: C1 with mixed phenotypes and favorable survival, C2 with metabolic activation and immune suppression, and C3 with immune activation and signaling dysregulation, which had the poorest outcomes. Mechanistically, we discovered that SPP1⁺ macrophages secrete PDGFB, which activates PDGFRB signaling in FADS1⁺ tumor cells to trigger epithelial-mesenchymal transition (EMT) and promote liver metastasis. This macrophage-tumor crosstalk was validated by single-cell transcriptomics, genetic perturbation, and coculture experiments. Collectively, our findings define a macrophage-derived PDGFB-PDGFRB axis that drives CRC liver metastasis and highlight a potential therapeutic target for overcoming metastatic progression and immune resistance.

Aim: To develop and validate prognostic nomograms incorporating peripheral blood lymphocyte counts and their dynamic changes in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy.

Methods: In this retrospective cohort study, consecutive patients with NPC who received radiotherapy at Chongqing University Cancer Hospital were included as the internal cohort (randomly divided 70 %/30 % for training and validation), while patients treated at Guangxi Medical University Cancer Hospital served as the external validation cohort. Prognostic nomograms for progression-free survival (PFS) and overall survival (OS) were constructed using multivariable Cox regression analyses.

Results: The internal and external cohorts comprised 746 and 138 patients, respectively. Age, gross tumor volume dose, neoadjuvant chemotherapy, clinical stage, plasma EBV-DNA level, baseline total T-cell count, and its post-treatment change (ΔT cells) were identified as independent prognostic factors. The nomograms demonstrated strong predictive performance, with concordance indices of 0.701, 0.716, and 0.714 for PFS, and 0.759, 0.735, and 0.734 for OS in the training, internal validation, and external datasets, respectively. The areas under the receiver operating characteristic curves for 3-year and 5-year PFS and OS exceeded 0.7 across all cohorts. Calibration plots indicated good agreement between predicted and observed outcomes, and decision curve analysis confirmed greater net clinical benefit compared with TNM staging and EBV-DNA-based models.

Conclusion: The proposed T-cell-based nomograms reliably predict PFS and OS in patients with NPC undergoing radiotherapy and were validated in an external cohort. These models provide improved prognostic discrimination beyond conventional staging systems and may assist in individualized risk stratification and management planning.

Head and neck squamous cell carcinoma (HNSCC) is the most prevalent histopathological subtype of head and neck malignancies. Owing to the lack of early specific symptoms, the majority of patients are diagnosed at intermediate or advanced stages, which is associated with an unfavorable prognosis and a substantial decline in quality of life. Radiomics, which leverages large-scale medical imaging data, enables the extraction of high-dimensional quantitative features through advanced image analysis, thereby providing deeper insights into tumor biology. In this review, we summarize recent advances in radiomics for the diagnosis, prognostic prediction, and evaluation of treatment-related toxicity in HNSCC. Furthermore, we highlight emerging applications of radiomics in genomics and proteomics, illustrating the associations between tumor molecular phenotypes and imaging-derived features. Finally, we discuss the challenges related to feature standardization and reproducibility, and outline the key limitations of current radiomics studies.

Objectives: This study explores the integration of radiomics features from contrast-enhanced CT and MRI with clinical and radiological risk factors for optimal prognosis models of disease-free survival (DFS) and overall survival (OS) in esophageal squamous cell carcinoma (ESCC).

Materials and methods: A retrospective study is undertaken of 371 ESCC patients who underwent contrast-enhanced CT and MRI with StarVIBE sequence, from September 2014 to December 2019. Prognosis models for DFS and OS were developed using cross-validation and Elastic-Net-Cox regression. Patients were grouped by treatment type (surgery, chemoradiotherapy, neoadjuvant therapy) to create single-modality and multi-modality models (Model-S, Model-CRT, and Model-nT). Model performance was evaluated using nomograms, calibration curves, and decision curves.

Results: Twelve optimal prognosis models were identified. For DFS, MRI c-indices were 0.595, 0.608, and 0.721, while CT c-indices were 0.686, 0.616, and 0.667. For OS, MRI c-indices were 0.692, 0.597, and 0.650, and CT c-indices were 0.656, 0.623, and 0.695. Multi-modality models demonstrated c-indices of 0.750, 0.695, 0.839 for DFS and 0.898, 0.777, 0.819 for OS.

Conclusion: Single-modality radiomics models exhibit limited predictive ability for DFS and OS in ESCC patients, whereas multi-modality radiomics models enhance predictive accuracy significantly.

Background: Photodynamic diagnosis (PDD) is widely used in bladder cancer management, enabling fluorescence-guided detection of lesions through intravesical administration of photosensitizers such as hexaminolevulinate (Cysview®/Hexvix®). Building on this clinical framework, we explored photodynamic therapy (PDT) using pheophorbide a (pheo), a chlorophyll-based photosensitizer, encapsulated in self-assembled poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO₅₀₀₀-PCL₄₀₀₀) micelles.

Results: In vitro assays were performed on human bladder cancer cell lines, namely the grade 3 invasive T24 and the grade 1 SW780, in both 2D monolayers and 3D spheroid cultures. In 2D, encapsulated pheo showed higher phototoxicity (IC₅₀: 129 nM T24, 156 nM SW780), while free pheo exhibited negligible effects, preventing IC₅₀ determination. Two-photon microscopy confirmed that encapsulation markedly enhanced pheo penetration, especially in T24. SW780 spheroids exhibited tight epithelial features and low permeability, forming characteristic microbladder-like vesicles. PDT reduced viability in both T24 and SW780 3D models, with a significant advantage for encapsulated pheo at day 6 post-treatment in T24 spheroids. Preliminary exploration in human tissue-engineered bladder tumor substitutes demonstrated the feasibility for PDT assessment in complex 3D environments, warranting further study.

Conclusions: These findings support polymer nanocarrier-mediated pheo delivery as a promising therapeutic approach and pave the way for integrated diagnostic-therapeutic strategies using existing intravesical platforms.

TLN1, a cytoskeletal protein associated with various tumors, remains inadequately studied in gliomas. In this study, we examined the functional role and mechanisms of TLN1 in glioma pathogenesis. Utilizing public databases, we conducted differential expression, survival (Kaplan-Meier/ROC), and regression analyses, which were subsequently validated with institutional datasets and clinical tissues. In vitro experiments demonstrated that TLN1 knockdown in glioma cells resulted in reduced proliferation (CCK8/EDU), migration and invasion (wound healing/Transwell), and increased apoptosis (AO/EB/flow cytometry); these findings were corroborated by Western blot analyses. Gene Set Enrichment Analysis (GSEA) linked TLN1 to the TGF-beta signaling pathway, a connection further validated by Western blot and in vivo murine models. Both public and institutional data indicated that TLN1 was upregulated in gliomas, with elevated expression correlating with poor prognosis. Furthermore, TLN1 knockdown inhibited glioma growth and progression in vitro and in vivo, primarily through the TGF-beta signaling pathway. Our findings establish TLN1 as an oncogenic driver in gliomas and highlight its potential as a therapeutic target.

Tumor Mutational Burden (TMB) is a widely used biomarker for selecting cancer patients for immune checkpoint inhibitor (ICI) therapy. However, TMB alone has limited predictive power, as it fails to account for the functional impact of mutations. We introduce AlphaTMB, a composite biomarker that integrates the quantity of mutations (TMB) with the qualitative assessment of their pathogenicity using AlphaMissense, a deep learning model that predicts the deleteriousness of missense variants. Using a pan-cancer cohort of 1,662 patients from the MSK-IMPACT study who received ICI therapy, we computed three scores per patient: TMB, Alpha (sum of AlphaMissense scores), and AlphaTMB (product of TMB and Alpha). Patients were stratified using both cancer-specific and pan-cancer quantiles. Survival outcomes were evaluated using Kaplan-Meier and multivariate Cox proportional hazards models, controlling for cancer type, age, and ICI regimen. AlphaTMB showed strong correlation with TMB (Spearman ρ = 0.866, p < 0.001), but offered improved prognostic accuracy. Patients in the bottom 80% AlphaTMB group had significantly poorer survival than those in the top 10% (HR < 2.51, p < 0.001), outperforming TMB and Alpha alone. AlphaTMB reclassified borderline cases, identifying subsets with low TMB but high deleterious mutation load, and vice versa. Gene mutation heatmaps and co-occurrence analysis confirmed that to 10% AlphaTMB-high tumors were enriched in mismatch repair and POLE mutations, reflecting a neoantigen-rich, immunotherapy-responsive phenotype. AlphaTMB improves survival prediction beyond TMB alone, better captures immunogenic tumor profiles, and reflects more accurate patient stratification. This AI derived somatic mutations pathogenicity scoring represents a step toward personalized immuno-oncology and merits further validation in prospective studies.

Nasopharyngeal carcinoma (NPC) is prevalent in Southeast Asia, including Taiwan. It exhibits higher morbidity as well as mortality in males than in females. However, the role of the androgen receptor (AR) in NPC remains unclear. In this study, AR expression was detected in most NPC cell lines and patient-derived xenografts. Treatment with enzalutamide, an antiandrogen, substantially inhibited patient-derived xenografts growth and demonstrated additive antitumor effects when combined with chemotherapy in AR-positive models. Additionally, transcriptome analysis following enzalutamide treatment revealed activation of hypoxia-inducible factor-1, steroid hormone, and AR pathways, alongside suppression of interferon and tumor necrosis factor pathways. Protein analysis further supported these transcriptomic changes. In AR-overexpressing NPC-B13 cells, AR appeared to regulate thyroid transcription factor-1 (TTF-1, encoded by NKX2-1 gene) and its downstream target epidermal growth factor receptor (EGFR), thereby promoting cancer cell proliferation. Furthermore, chromatin immunoprecipitation suggested that AR may directly bind to the NKX2-1 promoter to upregulate its mRNA expression. Under AR overexpression, Epstein-Barr virus (EBV) remained in a latent state, accompanied by suppression of lytic gene expression. Additionally, Epstein-Barr nuclear antigen-1 enhanced AR transactivation in a dose-dependent manner in NPC cell line reporter assays. Among 96 metastatic NPC tumor samples, AR expression was observed in 35 cases (36.5%), predominantly in males (33/83, 39.8%). AR expression correlated with poorer overall survival, with statistical significance noted in the full cohort and particularly in male patients. This study suggests that AR may promote metastatic NPC progression via the TTF-1/EGFR signaling pathway and interact with EBV to influence disease behavior, especially in males.

Gastric cancer (GC) remains a major global health concern due to its frequent late-stage diagnosis, persistent chemoresistance, and high metastatic potential, all of which contribute to poor clinical outcomes. TRIM26, an E3 ubiquitin ligase with emerging tumor-suppressive functions, has been implicated in various malignancies; however, its precise role in GC has not been fully elucidated. This study elucidates in ferroptosis and chemoresistance while uncovering stromal-tumor crosstalk mechanisms underlying its suppression. Using public databases and clinical GC specimens and established cell lines (MGC-803, HGC27, MKN45), we observed significant downregulation of TRIM26 expression in tumor tissues compared to adjacent normal counterparts (p < 0.001), which correlated with advanced clinical stage and unfavorable prognosis. Functional assays including CCK-8, wound healing, colony formation, and Transwell migration, demonstrated that TRIM26 knockdown significantly enhanced GC cell proliferation, migration, and invasion, whereas TRIM26 overexpression reversed these malignant phenotypes. Mechanistically, TRIM26 induced ferroptosis via HSF1 ubiquitination and degradation, leading to reduced glutathione (GSH) levels and elevated levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Additionally, we identified cancer-associated fibroblast (CAF)-derived exosomal miR-24-3p as a key upstream regulator that directly targets the 3' untranslated region (3' UTR) of TRIM26, thereby suppressing its expression, as confirmed by luciferase reporter assays. In cisplatin-resistant GC models (MGC803/DDP and AGS/DDP), prolonged cisplatin exposure resulted in a pronounced reduction in TRIM26 expression, corresponding with a 5.6-fold increase in IC₅₀ and a heightened metastatic profile. TRIM26 silencing further potentiated chemoresistance and invasive behavior, which coincided with epithelial-mesenchymal transition (EMT), as evidenced by decreased E-cadherin and increased N-cadherin and Vimentin expression. In contrast, TRIM26 restoration re-sensitized resistant GC cells to cisplatin and mitigated their metastatic capacity. Collectively, these findings reveal TRIM26 as a pivotal suppressor of GC progression, acting through the regulation of ferroptosis and EMT while being modulated by stromal exosomal miR-24-3p Therapeutic strategies aimed at restoring TRIM26 expression or disrupting the miR-24-3p/TRIM26/HSF1 axis may offer promising avenues for overcoming chemoresistance and limiting metastasis in GC.

Tumor-associated mast cells in the tumor microenvironment play a critical and complex role in the progression of tumor malignancy. However, the key molecules that control mast cell activation and target the biological function of ovarian cancer (OC) cells are still not fully understood. In this study, we performed scRNA-seq on cells isolated from six cases of epithelial OC tissues (three cases of primary tumor and three of metastatic tumor), and we identified three mast cell subtypes, among which the proportion of the second group of mast cell subsets specifically expressing NR4A3 was significantly higher in the metastatic tissue than in the primary tissue, suggesting that NR4A3 expression of MC may be related to the metastasis and prognosis of OC. In vitro, the biological functions of constructed NR4A3^high bone-marrow-derived mast cells, such as degranulation response, showed a significant decline, but their secretion of high levels of CXCL16 and IL-8 promoted the polarization of macrophages to M2 through the STAT6 pathway, thus promoting the migration and invasion of OC. In ovarian tumor models in mice with mast cell deficiency (c-Kit W-sh/ W-sh), adoptive transfer of NR4A3^high mast cells can not only promote subcutaneous tumor growth, but also promote intraperitoneal tumor cell colonization, decrease the ratio of CD8+ T cells, and increase the ratio of M2 macrophages. These results indicate that NR4A3 can drive mast cells to release more CXCL16 and IL-8 and induce macrophage M2 polarization through STAT6 signaling pathway, thereby mediating the metastasis of ovarian cancer.