Gliomas exhibit considerable molecular heterogeneity and immunological complexity, emphasizing the need for effective biomarkers and therapeutic targets. In this study, the Chinese Glioma Genome Atlas (CGGA-325/693) and The Cancer Genome Atlas (TCGA-LGG/GBM) cohorts were used to explore the pathological role of PHD finger protein 23 (PHF23) in gliomas. Machine learning algorithms were performed to construct a PHF23-related prognosis signature (PHF23-RPS). Our analysis revealed significant upregulation of PHF23 in high-grade gliomas, while the PHF23-RPS exhibited strong predictive performance (AUC = 0.853). Two molecular subtypes were identified; Cluster 2 was characterized as "inflamed yet immunosuppressive". This subtype displayed a tumor mutational burden (TMB) paradox, where elevated TMB failed to translate into survival benefits due to extensive M2 macrophage infiltration and checkpoint-mediated immune exhaustion. Pharmacogenomic screening and molecular dynamics simulations identified Entospletinib as a potential candidate targeting this immunosuppressive barrier, showing a stable binding affinity (-7.7 kcal/mol). Functional assays, including in vitro experiments and in vivo experiments via a male BALB/c nude mouse orthotopic glioma model (n = 6/group), confirmed that PHF23 silencing inhibited glioma malignancy. Our results identify PHF23 as a critical oncogenic driver in glioma and support the PHF23-RPS for risk stratification. Entospletinib may offer a potential immunomodulatory option for high-risk gliomas.

Colorectal cancer (CRC) is a prevalent malignant tumour, with its incidence and mortality rates consistently ranking among the highest and exhibiting an upward trend. Extensive screening and early diagnosis are crucial for managing CRC progression and improving patient prognosis. This study aims to construct a novel analytical framework for integrating the sequencing data from tumour tissue and peripheral blood. By integrating and analysing the multi-omics data and clinical data from tumour tissues and peripheral blood, we confirmed that the LTB4R gene is significantly upregulated not only in tumour tissues but also in the peripheral blood of CRC patients. Further single-cell RNA sequencing (scRNA-seq) and immune cell correlation analyses revealed that Leukotriene B4 receptor 1 (LTB4R) is primarily expressed in macrophages, T cells, and other immune cells, with a significant negative correlation observed with M1-type macrophages, suggesting its potential pro-tumourigenic role in CRC by suppressing M1 macrophage. Additionally, simulated gene knockout analysis (scTenifoldKnk) demonstrated that LTB4R knockout significantly impacts immune-related pathways, including immune response and immune receptor activity. These findings not only highlight the potential of LTB4R as a peripheral blood diagnostic marker for CRC but also elucidate its involvement in tumour progression, offering novel insights for early clinical diagnosis and tumour screening systems.

Chemotherapy has significantly improved survival in breast cancer and, in the neoadjuvant setting, contributes to tumor downstaging and increased rates of breast-conserving surgery while enabling in vivo assessment of tumor biology and chemosensitivity. Pathological complete response (pCR) is a key endpoint associated with favorable outcomes; however, tumor heterogeneity highlights the need for reliable predictive biomarkers. This study evaluated the mRNA expression of 13 candidate genes in relation to molecular subtypes and pathological response to neoadjuvant chemotherapy (NAC) to identify potential predictive and prognostic markers. Pretreatment core biopsies from 92 patients receiving NAC were analyzed by quantitative RT-PCR. Molecular subtypes were determined by immunohistochemistry (ER, PR, HER2, Ki67), and pathological response was classified using the Miller-Payne scale as good (MP 4/5) or poor (MP 1-3). Multivariate logistic regression assessed associations between gene expression, subtype, and pCR. Hormone receptor-positive tumors showed significantly higher expression of AXL, FGFR1, RAP80, GAS6, BTRCP, and ZNF217. Significant associations with pCR were observed for AXL, FGFR1, YAP, and BRCA1. Low AXL and BRCA1 expression levels were independently associated with pCR. In addition, their combined low expression was associated most strongly with breast pCR in this cohort. These findings should be interpreted as exploratory and require validation in independent cohorts.

Solid tumor research is undergoing a decisive transition: innovation is no longer simply "finding a new receptor" or "inhibiting a new enzyme", but integrating targets, biomarkers, and therapeutic modalities into strategies capable of anticipating tumor adaptation and therefore mechanisms of resistance [...].

Nuclear mechanics and mechanotransduction are involved in the migration and invasion process, such as those in which the cells need to deform themselves to pass through constrictions. Specifically, properties like nuclear softness, viscoelasticity, plasticity (like nuclear pore complexes) and deformability are critical in cancer and its malignant progression. The nucleus represents a physical barrier for the migration and invasion in dense 3D extracellular matrix (ECM) scaffolds. Therefore, the deformability of the nucleus seems to determine the migration limit in circumstances where the enzymatic remodeling of the surroundings is impaired. There are still significant knowledge gaps regarding effects of nuclear deformation during cancer dissemination. It seems that nuclear deformation can alter gene transcription, induce alternative splicing processes, impact nuclear envelope rupture, nuclear pore complex dilatation, damage the DNA, and increase the genomic instability. These mechanically induced alterations can in turn impact the migratory behavior of the cancer cells. The stiffness of the nucleus relies on the condensation of chromatin, and the nuclear lamina, which consists of a network of intermediate filaments underneath the nuclear envelope. All of this is discussed in the review and it is argued that nuclear deformability is universally found in various cancer types. Another focus is placed on the nuclear envelope proteins like emerin, and the SUN-KASH complex and how they contribute to the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which consequently couples the nucleus and the cytoskeleton. It is argued that this connection is crucial for force transmission, which governs nuclear stiffness dynamically, depending on the force applied. In this review, recent findings are described that couple ECM-induced nuclear mechanosensing and mechanotransduction with the migration and invasion of cancer cells. Moreover, it is suspected that changes in the mechanosensory characteristics of the cell nucleus could play a pivotal part in the malignancy of cancer cells and the heterogeneity of tumors. Finally, it is discussed what impact the individual elements of the nucleus offer to mechanically alter cellular migration and invasion in cancer and its malignant progression.

PAX3 plays a vital role in regulating proper growth, migration, differentiation, and survival during development of normal tissues, including those derived from the embryonic neural crest. PAX3 is a transcription factor with two separate DNA-binding domains and can positively (and less frequently, negatively) regulate gene expression. The levels of PAX3 can be modified by upstream molecular pathways, and its subsequent downstream functions are regulated through a wide range of protein interactions and posttranscriptional modifications. PAX3 direct downstream target genes are other transcription regulators and factors that modulate cellular proliferation, lineage specificity, migration, and survival. The pathways that PAX3 regulates during development may be recycled and subverted during disease progression, for example, during cancer progression, growth, and metastasis. Indeed, PAX3 is overexpressed in several cancers, including melanoma, neuroblastoma, and rhabdomyosarcoma. While there is still much that is unknown about the mechanisms by which PAX3 controls such a wide array of key cellular functions, a great deal of progress has been made to advance our understanding of this critical and multi-faceted factor.

Xeroderma pigmentosum group B (XPB/ERCC3) and group D (XPD/ERCC2) helicases are integral components of the transcription factor IIH (TFIIH) complex, coordinating DNA unwinding during transcription initiation and nucleotide excision repair (NER). XPB functions as an ATP-driven translocase that generates torsional strain to promote promoter melting and DNA opening at lesion sites, whereas XPD acts as a 5' to 3' helicase responsible for lesion verification and extension of the repair bubble. Structural and biochemical studies have clarified how TFIIH subunits regulate these helicases-p52 and p8 modulate XPB's translocation activity, while p44, p62, and MAT1 control XPD's helicase function through conformational and compositional transitions within the complex. Beyond their canonical roles, XPB and XPD participate in diverse cellular pathways, including cell-cycle regulation and oxidative stress response, highlighting their involvement in maintaining genome integrity beyond repair and transcription. Mutations in either helicase lead to xeroderma pigmentosum (XP), trichothiodystrophy (TTD), or combined XP/Cockayne syndrome (XP/CS) phenotypes, emphasizing the essential role of TFIIH integrity for human health. Recent biochemical and pharmacological advances have further revealed the therapeutic relevance of these helicases-XPB as a target of small-molecule inhibitors such as triptolide, Minnelide, and spironolactone, and XPD as a potential modulator of cancer sensitivity to DNA-damaging treatments. Collectively, XPB and XPD exemplify the structural and functional versatility of TFIIH helicases across repair, transcription, and genome maintenance.

Colorectal cancer (CRC) remains one of the most important causes of cancer-related mortality worldwide, underscoring the need to better understand systemic inflammatory pathways across the colorectal neoplasia spectrum. In this exploratory case-control study, we characterized plasma levels of key inflammatory mediators in healthy individuals and patients with colorectal polyps or CRC. Healthy controls (n = 10), patients with colorectal polyps (CP, n = 16), early-onset CRC (EO-CRC, n = 11), and late-onset CRC (LO-CRC, n = 51) were prospectively enrolled. Plasma levels of sTNF-R, total TNF-α, PDGF-AA, IL-17A, and IL-1β were measured by ELISA. Group comparisons used Kruskal-Wallis tests with epsilon-squared effect sizes. PDGF-AA showed the strongest differences between controls and all neoplastic groups (ε2 ≥ 0.15), and these comparisons remained significant after Benjamini-Hochberg false discovery rate correction. IL-17A levels were slightly higher in EO-CRC than in LO-CRC; however, this difference did not remain significant after adjustment for multiple testing. TNF-α and IL-1β showed no significant differences across groups. Overall, this study primarily provides descriptive and hypothesis-generating evidence of differential inflammatory patterns across colorectal neoplasia, with PDGF-AA emerging as the most robust signal in this exploratory dataset. These findings do not support immediate diagnostic application and require validation in larger, prospectively recruited cohorts.

We have previously identified MACC1 and IER2 as functional biomarkers in the context of colorectal cancer. In silico correlation analysis suggested a possible functional connection between the expressions of these biomarkers, given that a significant positive correlation between IER2 and MACC1 RNA was observed. In loss- and gain-of-function experiments, we found that MACC1 positively regulates the expression of IER2. Furthermore, pulldown experiments provided evidence for MACC1-IER2 protein-protein interactions. Functionally, MACC1 enhanced proliferation of HCT116 cells overexpressing IER2 but not of HCT116 cells with knockdown of IER2 expression. Patients with high expressions of both biomarkers lived significantly shorter, whereas those with low concentrations of both markers showed the longest survival. Taken together, these findings show a functional interplay between the colorectal biomarkers MACC1 and IER2, which, in turn, has an impact on the survival of colorectal cancer patients.

Cancer is a dynamic and evolving biological system [...].

Apigenin, a naturally occurring flavonoid with low toxicity, exhibits anticancer activity, yet its effects on microRNAs (miRNAs) and downstream gene networks in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we evaluated apigenin's antitumor effects in TE-1 and Eca-109 cells, assessing proliferation, apoptosis, colony formation, and invasion. Differentially expressed miRNAs were identified via small RNA sequencing, and candidate target genes were predicted, annotated using GO and KEGG analyses, and validated by qRT-PCR, revealing miRNA-mediated regulatory mechanisms underlying apigenin's inhibitory effects in ESCC. Apigenin markedly suppressed cell proliferation, clonogenic growth, wound closure, and invasive capacity, while promoting apoptosis in a dose-dependent manner. In TE-1 cells, apigenin upregulated hsa-let-7c-3p, hsa-miR-374c-3p, hsa-miR-3177-3p hsa-miR-4454, and hsa-miR-4728-3p, while downregulating hsa-miR-573, hsa-miR-548az-5p, hsa-miR-33b-5p, hsa-miR-4479, and hsa-miR-3198. Correspondingly, tumor-associated target genes including ALDH3A2, SEMA3F, MAP4K5, and TRIP13 were upregulated, whereas PIK3IP1, AGO2, MMP2, and RALBP1 were suppressed. In Eca-109 cells, apigenin altered the expression of distinct miRNAs, including the upregulation of hsa-miR-891-5p, hsa-miR-3170, hsa-miR-4421, and hsa-miR-675-5p and the downregulation of hsa-miR-153, hsa-miR-3188, and hsa-miR-4435, thereby modulating key oncogenic targets such as MAPK1, SALL4, and COX15. Functional enrichment analyses indicated that apigenin-regulated genes are involved in multiple cancer-related pathways across cytoplasmic and nuclear compartments. Overall, these results suggest that apigenin suppresses ESCC progression via coordinated miRNA-mRNA regulation, highlighting its potential as a therapeutic agent.

Molecular subtypes are potential prognostic and predictive tools in muscle-invasive bladder cancer (MIBC). However, subtype concordance between primary tumors and metastases, as well as subtype-specific differences in metastatic patterns, remain poorly characterized. The present study aimed to evaluate the concordance of molecular subtypes between primary tumors and matched lymph node (LN) metastases and to explore their association with metastatic patterns. Gene expression-based molecular subtypes were determined according to the five-tiered Lund Taxonomy in 182 primary tumor samples and 34 matched LN metastases from patients with MIBC who underwent upfront radical cystectomy. Subtypes identified in the primary tumors were compared with those in matched positive LNs and patterns of distant metastasis were analyzed. In addition, the association between molecular and histological subtypes was also investigated. We found an overall 62% subtype concordance between primary tumors and corresponding LN metastases, with complete concordance in the basal/squamous subtype, lower concordance in the luminal subtypes (genomically unstable: 67%; urothelial-like: 57%), and low concordance (33%) in the mesenchymal-like (Mes) subtype. Luminal subtypes were associated with LN-only metastases and less frequent distant metastases. In contrast, the Mes subtype was associated with a higher rate of distant metastases (43%), and more frequent multiorgan involvement (≥3 organs: 40%). Higher expression of the mesenchymal gene CDH2 and the neuronal-differentiation genes GNG4 and ENO2 was associated with a higher number of metastatic sites. Gene expression-based molecular subtypes may change between primary MIBCs and matched LN metastases, and these differences appear to be subtype-dependent. Mes subtype and the expression of CDH2 as well as GNG4 and ENO2 are associated with more frequent and extensive metastases, indicating highly aggressive forms of MIBC.

Peritoneal metastases (PM) occur in 10% of patients with colorectal cancer (CRC) and are linked to poor outcomes. Although dysregulated innate lymphoid cells (ILC) have been described in CRC, their function in CRC-PM remains unclear. Here, we analyze tumor samples from CRC and CRC-PM patients using single-cell RNA sequencing (11 patients), flow cytometry (8 patients) and differentiation assays (24 patients). Healthy colon, primary CRC and CRC-PM tumors are infiltrated by heterogeneous populations of ILC3, ILC2, ILC1, tissue resident (tr)NK cells and conventional (c)NK cells. Compared to healthy colons, primary CRC and CRC-PM tumors are depleted of ILC3 but enriched for ILC1, trNK cells and cNK cells. CRC and CRC-PM tumors harbor two immature ILC populations, early NK and naïve (n)ILC, with nILCs being transcriptionally skewed toward ILC1 and trNK cells. Indeed, co-culture of isolated nILCs with OP9-DL1 cells induces intratumoral nILC differentiation into ILC1/trNK-like cells. These findings help understand the immune pathogenesis of CRC and CRC-PM and provide insights for future ILC1 and NK cell-based therapies.

Immune evasion driven by aberrant PD-L1 expression poses a significant challenge to the efficacy of cancer immunotherapy. Although Mitofusin-2 (MFN2) is recognized for its role in tumor suppression, its specific contribution to the regulation of immune escape remains poorly understood. Here, we integrated analyses of public datasets, clinical specimens, and mechanistic experiments in multiple cancer cell lines, immunocompetent mouse models, and patient-derived organoids. A combination of molecular assays and single-cell transcriptomic reanalysis was employed to elucidate how MFN2 influences tumor immune escape. MFN2 expression was markedly reduced in various cancers and inversely correlated with PD-L1 levels and immunosuppressive gene signatures. Functional assays demonstrated that MFN2 suppresses PD-L1 transcription by limiting EGFR-dependent activation and nuclear translocation of STAT3. Loss of MFN2 enhanced PD-L1 expression, impaired CD8+ T-cell cytotoxicity, and accelerated tumor growth in immunocompetent mice. Conversely, restoration of MFN2 or pharmacological inhibition of STAT3 decreased PD-L1 expression and reactivated antitumor immunity. Our findings identify MFN2 as a critical suppressor of tumor immune evasion through the EGFR/STAT3-PD-L1 signaling pathway. Targeting this axis may offer a novel strategy to enhance the efficacy of PD-1/PD-L1-based immunotherapy.

Osteosarcoma, the most common primary malignant bone tumour, presents significant treatment challenges due to its complex tumour microenvironment and the development of chemoresistance. This study employs single-cell transcriptomics to investigate chemotherapy-induced changes in osteosarcoma at both the cellular and molecular levels. Single-cell RNA sequencing data were analysed to identify cell subpopulations and their responses to chemotherapy. Differential gene expression and pathway enrichment analyses were performed to elucidate chemotherapy-induced changes. Additionally, we developed and validated a predictive model based on pyroptosis-related genes, named Pyroscore, using 101 different machine-learning algorithms. Chemotherapy led to an increased proportion of osteoclasts, endothelial cells, mesenchymal stem cells and pericytes, while decreasing T and NK cells, B cells, chondroblasts, monocytes and macrophages. Chemotherapy markedly upregulates the pyroptosis pathway in tumour cells, suggesting that chemotherapy induces programmed cell death in cancer cells through the activation of pyroptosis. Metabolic pathway analysis revealed significant inhibition of sulphur metabolism, starch and sucrose metabolism, pentose phosphate pathway, inositol phosphate metabolism, nitrogen metabolism and fatty acid metabolism. The Pyroscore model, which incorporates BAK1, CASP1, CASP5 and CASP6, demonstrated robust prognostic value across multiple data sets, with high scores correlating with improved survival outcomes. This study highlights the impact of chemotherapy on osteosarcoma cell subpopulations and the tumour microenvironment. The activation of the pyroptosis pathway and the development of the pyroscore prognostic model provide new insights into the mechanisms of chemotherapy response and potential therapeutic targets. These findings underscore the importance of personalized treatment strategies in improving outcomes for osteosarcoma patients.

Hongwu mixture (HWM) consists of Taxus chinensis, Marsdenia tenacissima, Rhizoma Curcumae, and Semen coicis. The objective of this study was to ascertain the potential role of the Hongwu mixture (HWM) in the treatment of triple-negative breast cancer (TNBC). TNBC cells were treated with low, medium, and high doses of HWM, and CCK-8 assays were conducted to evaluate the impact of different doses of HWM on TNBC cell viability. The target molecules of HWM were predicted using RNA-sequencing, and molecular docking models between HWM components and target proteins were developed. As the dose of HWM increased, TNBC cell viability gradually decreased. HWM inhibited the proliferation and mobility of TNBC cells, slowed the tumor growth, and upregulated the apoptosis of TNBC cells. HWM promoted Zinc finger protein 143 (ZNF143)-mediated transcriptional activation of salvador family WW domain-containing protein 1 (SAV1) by stabilizing ZNF143 protein expression, leading to phosphorylation of large tumor suppressor homolog 1 (LATS1) and Yes-associated protein 1 (YAP1). Knockdown of ZNF143/SAV1 signaling impaired the therapeutic effect of HWM, and treatment with verteporfin, pharmacological inhibition of YAP/TAZ, reversed the effects of knockdown of SAV1. Therefore, HWM might offer a potent strategy for managing TNBC effectively.

Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes a subset of prostate cancers but it is not understood how cells adapt to declining activity of this major transcription elongation kinase. To probe this response, we developed a cell line resistant to an inhibitor targeting CDK12 and its paralog, CDK13. CDK13 can compensate for the loss of CDK12, which is why we used the dual inhibitor THZ531. Targeted drug screening of the parental and resistant cell lines revealed cross-resistance to other transcriptional kinases but no clear acquired point of vulnerability. Using genome-wide mapping of mRNA-stabilization based on metabolic labelling of RNA, we report selective mRNA stabilization of factors promoting oxidative phosphorylation in the resistant cells. We go on to show that loss of CDK12 activity enhances ATP production both in cell line models and in patient tumours. Finally, we show that dual inhibition of CDK12/13 results in excessive phosphorylation of the DNA damage H2AX in prostate cancer cells but not in our CDK12/13 inhibitor-resistant model system. In brief, we propose that inactivation of CDK12 rewires cellular energy metabolism to suppress DNA damage.

Hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative breast cancer associates with a sustained risk of relapse over time. Current multigene assays offer limited validity to identify clinically low-risk tumors at high risk of recurrence, which is particularly relevant in the context of novel adjuvant therapies. In this study, we developed and validated ER-Predict, a machine learning assay leveraging a 14-gene expression signature to classify early stage HR-positive/HER2-negative breast cancer according to the risk of relapse.

Next-Generation Sequencing (NGS) allows the use of more efficacious targeted treatments for lung cancer; however, sample inadequacy can cause delays in patient pathways. Here, we compare various methods of tissue acquisition used in clinical practice and identify factors associated with inadequate sampling.

Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) remains a substantial clinical obstacle in treating lung adenocarcinoma (LUAD). Identifying pro-survival pathways that allow tumor cells to evade TKI-induced apoptosis is critical for overcoming this resistance. The transcriptional repressor transducin-like enhancer of split 1 (TLE1) was previously identified as a crucial oncogenic factor that promotes survival in resistant cells. This study investigates the mitochondrial protein Bcl-2 inhibitor of transcription 1 (Bit1) as a key pro-apoptotic signal that overrides the TLE1-mediated survival program.