Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator implicated in tumor progression; however, its expression pattern and subcellular localization across different stages of endometrial carcinogenesis remain incompletely characterized. This study evaluated EZH2 expression in two biologically distinct endometrial carcinoma cell lines (Ishikawa and MFE-319) and in archived human endometrial tissues representing proliferative and secretory endometrium, hyperplasia, and Type I and Type II endometrial carcinomas. Histopathological evaluation was performed using hematoxylin and eosin staining. EZH2 expression was assessed by immunocytochemistry and Western blot analysis in the cell lines and by immunohistochemistry in tissue specimens, while apoptosis was evaluated by TUNEL assay in tissue samples. MFE-319 cells demonstrated significantly higher EZH2 expression than Ishikawa cells (H-score: 352.9 ± 78.9 vs. 137.6 ± 31.5, p < 0.0001), and Western blot analysis confirmed the same direction of change. Among tissue specimens, the highest EZH2 immunoreactivity was observed in Type II endometrial carcinoma (366.0 ± 63.7), with significantly higher expression than proliferative endometrium (231.5 ± 59.3), secretory endometrium (190.5 ± 52.4), and hyperplasia without atypia (261.0 ± 56.9), whereas no significant differences were detected among several intermediate histopathological groups. Nuclear localization of EZH2 became more prominent in atypical hyperplasia and carcinoma tissues. Apoptotic indices were significantly higher in both Type I and Type II carcinomas than in normal endometrium and hyperplasia groups, representing an association with increased EZH2 expression rather than evidence of a direct mechanistic relationship. These findings demonstrate that EZH2 expression differs across histopathological categories of endometrial lesions, with the highest expression observed in Type II endometrial carcinoma. The observed predominance of nuclear EZH2 in atypical hyperplasia and carcinoma further supports its association with aggressive tumor biology, although additional functional and clinicopathological studies are required to establish its clinical and biological significance.

Traditional histological classification of meningiomas has low prognostic accuracy and necessitates integration of molecular biomarkers. However, current data are fragmented and require rigorous synthesis.

Soft tissue tumors with chondroid matrix represent a heterogeneous group with persistent diagnostic challenges. Advances in molecular diagnostics have identified recurrent gene fusions in several chondroid neoplasms, predominantly involving FN1. Here, we report two cases of chondroid tumors harboring a novel FOS::PABPN1 fusion. The patients were young and presented with small, deep, peri-osseous nodules located in the extremities. Histologically, the tumors were well-circumscribed and lobulated. Both cases presented fibro-cartilaginous and spindle cell areas. No cytonuclear atypia, mitoses, or necrosis were observed. Immunohistochemistry (performed in Case 2) revealed positivity for S100, CD34, and FOS, with negativity for MDM2, HMGA2, PLAG1, and desmin. RNA sequencing identified an identical in-frame FOS::PABPN1 fusion transcript in both tumors. Unsupervised transcriptomic clustering positioned the cases near synovial chondromatoses and other chondroid lesions, despite the absence of FN1 rearrangements. Massive overexpression of the WIF1 (Wnt Inhibitory Factor1) gene was also observed. To our knowledge, this is the first description of FOS rearrangement in mesenchymal tumors exhibiting chondroid differentiation. The FOS::PABPN1 fusion expands the spectrum of FOS-altered neoplasms beyond osteoblastic and vascular lesions and defines a potential new molecular subset of benign chondroid tumors. These findings highlight the utility of RNA sequencing in the diagnosis of chondroid neoplasms in order to identify rearrangement (of FN1, THBS1 or FOS) or IDH1/2. The consistent upregulation of WIF1 may represent a potential diagnostic biomarker.

Colorectal cancer is a common gastrointestinal malignancy worldwide. KRAS gene mutation is an important molecular feature of colorectal cancer, but the clinical significance of different mutation sites remains unclear. This study aims to investigate the distribution characteristics of specific KRAS gene mutation sites and analyze their associations with clinicopathological parameters and survival outcomes in patients with colorectal cancer, thereby providing a basis for precise stratified diagnosis and treatment.

Osteosarcoma (OS) is a malignant bone tumor that predominantly affects adolescents. Due to its early metastatic tendency and chemoresistance, long-term survival rates in patients have not shown significant improvement over time, highlighting the urgent need for novel molecular targets and therapeutic strategies. Ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, offers a promising avenue for overcoming drug-resistant tumors. ATP-binding cassette subfamily B member 6 (ABCB6) belongs to the ATP-binding cassette (ABC) transporter superfamily and is mainly localised to the outer mitochondrial membrane, where it participates in haem synthesis and intracellular iron transport. Recent studies have indicated that ABCB6 is aberrantly expressed in various malignancies and regulates tumor progression, yet its role and mechanism in OS remain unexplored. The present study aims to systematically characterise the expression pattern, clinical prognostic significance, and biological functions of ABCB6 in OS, and to dissect the molecular mechanism by which ABCB6 governs ferroptosis in OS cells, thereby providing a theoretical foundation for ABCB6-targeted therapy.

Anaplastic lymphoma kinase (ALK) fusions are established oncogenic drivers and therapeutic targets in multiple malignancies, including non-small cell lung cancer, but are rare in colorectal cancer (CRC). Although ALK fusions in CRC have been associated with sensitivity to ALK inhibitors, their broader genomic context remains incompletely defined. We aimed to characterize the prevalence, clinicogenomic features, and therapeutic implications of ALK fusions in advanced CRC.

Isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion are key molecular markers for glioma classification. Amide proton transfer weighted (APTw) and nuclear Overhauser effect-weighted (NOEw) markers showed promise for glioma characterization, by probing protein-related tissue properties. However, their interpretation is confounded by direct water saturation, macromolecules (semi-solid magnetization transfer-ssMT), and T1 relaxation. Here, we aimed to assess the performance of three APTw and NOEw metrics-uncorrected, spillover/ssMT-corrected (FMC), and fully spillover/ssMT- and T1-corrected (FMTC)-for glioma stratification. Fifty patients with suspected gliomas were prospectively enrolled (12 IDH-wild-type, 38 IDH-mutant, of which 21 with 1p/19q codeletion). Acquisitions were performed at 3 T using a 3D gradient echo readout with chemical exchange saturation transfer (B1 = 2 μT for APTw, 0.6 μT for NOEw; T1sat = 2 s), WASABI (WAter Shift And B1) for B0/B1 mapping, and saturation recovery for T1 mapping. Glioma subtypes were compared using metrics extracted from manually segmented masks, using two-tailed Mann-Whitney U tests, and the Benjamini-Hochberg false discovery rate (FDR) correction. Effect sizes were quantified using Cliff's δ with 95% bootstrap confidence intervals and classification performance was assessed by receiver operating characteristic analyses (area under the curve, AUC). IDH-mutant and wild-type gliomas differed significantly for the uncorrected APTw metric (p = 0.005, AUC = 0.79), with stronger discrimination following correction-APTw-FMC (p < 0.001, AUC = 0.94) and APTw-FMTC (p < 0.001, AUC = 0.96), both with large effect sizes. Only APTw-FMTC distinguished 1p/19q codeleted from non-codeleted gliomas before FDR correction (uncorrected p = 0.01, AUC = 0.74). The NOEw metrics did not differ between any molecular subgroups, likely due to limited sensitivity of this contrast at 3 T. These results suggest that correcting for fluid, ssMT, and T1 effects enhances the accuracy of APTw metrics, offering a more robust and biophysically grounded approach to noninvasive glioma diagnosis.

Epidermal growth factor receptor (EGFR) mutation status plays a critical role in guiding targeted therapy for non-small cell lung cancer (NSCLC). However, molecular testing in patients with stage IA NSCLC may be limited by insufficient tissue availability, procedural invasiveness, and resource constraints. Therefore, developing a non-invasive approach for EGFR mutation prediction is of substantial clinical interest. This study aimed to develop a computed tomography (CT) radiomics based model integrating clinical variables for non-invasive prediction of EGFR mutation status in stage IA NSCLC patients.

Many tumours show deficiencies in DNA damage response (DDR), not only driving tumorigenesis but also exposing vulnerabilities with therapeutic potential. Assessing which patients might benefit from DDR-targeting therapy requires knowledge of tumour DDR deficiency (DDRd) status, with mutational signatures reportedly better predictors than loss-of-function mutations. Existing DDRd models offer effective prediction for pathways with well-characterized processes and mutational signatures. Nevertheless, development of models for additional DDRd and clinically relevant mechanisms could be hampered by the fact that most mutational signatures have unknown etiology. Using supervised non-negative matrix factorization (SNMF), we integrate mutational signature learning with multiclass DDR-deficiency prediction to enable etiology-guided learning of signatures from cell lines with confirmed gene knockouts. Applied to DDR gene knockout human-induced pluripotent stem cell lines, SNMF identified etiology-aligned representations of deficiency in homologous recombination, mismatch repair, and base excision repair. Even guided by pathway-level labels, SNMF captured gene-specific base excision repair submechanisms, showing the integration offered added granularity. Learned cell line signatures showed high similarity to tumour-derived COSMIC signatures, revealed associations with mutations in DDR genes, and enabled high recall of tumours with DDR deficiencies. We envision that SNMF-like methods could leverage knockout screens to learn etiology-guided signatures for improved DDRd annotation and treatment optimization. SNMF is available at: https://github.com/joanagoncalveslab/SNMF.

V gene segments of the T cell receptor (TCR) β chain (TRBV) are crucial for antigen recognition, yet previous studies have treated them as fixed categories and neglected repertoire-specific immune dynamics that inform functional diversity.

Barrier-to-Autointegration Factor 1 (BANF1) is a self-associating protein encoded within the q13.1 locus of chromosome 11. It is integral to multiple cellular processes, including cell cycle regulation, chromatin organization, gene expression modulation, nuclear envelope (NE) repair, DNA damage repair (DDR), innate immune function, and viral infection control. While prior investigations have provided preliminary phenotypic and bioinformatic characterizations of BANF1 across various disease states, comprehensive analyses detailing its functional roles and mechanistic underpinnings in diverse pathological contexts remain scarce. In cancer, BANF1 is frequently upregulated, with cancer cells leveraging its functions to preserve NE integrity, inhibit activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) immune pathway, and facilitate epithelial-mesenchymal transition (EMT). These activities contribute to enhanced genomic stability and promote tumor cell proliferation and migration, thereby conferring oncogenic properties. In neurodegenerative diseases, BANF1 is implicated in disease pathogenesis, exemplified by its mediation of glutamate-induced oxidative stress and apoptosis in neuronal cells, as observed in Alzheimer's disease (AD). Additionally, rare mutations in BANF1 are associated with hereditary conditions: the recessive Ala12Thr (A12T) variant causes Néstor-Guillermo progeria syndrome (NGPS), whereas the dominant Gly16Arg (G16R) mutation results in dominant motor neuronopathy. This review further synthesizes recent progress in exploring BANF1 as a therapeutic target, encompassing the development of small-molecule inhibitors, immunomodulatory approaches, and its potential applications in cancer treatment. Overall, this article provides a comprehensive overview of BANF1's structural features, cellular functions, and involvement in disease initiation and progression, with particular emphasis on its expression profiles in malignancies and the therapeutic promise of BANF1-directed interventions.

Primary liver cancer is a major global cause of cancer death, and hepatocellular carcinoma (HCC) is the predominant histological subtype. This literature review synthesizes current evidence on the exposome, multi-omics landscape, and artificial intelligence (AI)-based integration strategies relevant to biomarker discovery in liver cancer, with a focus on biological rationale, emerging clinical applications, and translational limitations. Key etiologic drivers include viral hepatitis, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease, all of which interact with environmental exposures across the life course. Biomarker discovery increasingly relies on integrated assessment of exposure-related signals together with genomic, epigenomic, transcriptomic, proteomic, metabolomic, and spatially resolved data. Hepatocarcinogenesis involves a complex interplay of chronic liver injury, environmentally patterned molecular perturbation, and dynamic tumor-host interactions. We emphasize an exposome-informed, multimodal strategy in which interpretable AI models identify clinically relevant signatures for early detection, prognostic stratification, and treatment guidance. Critical limitations of current evidence include incomplete exposure assessment, heterogeneous data platforms, retrospective study design, limited external validation, and insufficient model transparency. Emerging approaches, including proteogenomic, lipidomic, single-cell, and digital pathology-based modeling, show promise but require further validation in etiologically diverse cohorts. The purpose of this review is to critically examine how AI can integrate exposome-related information with multi-omics data for biomarker discovery in liver cancer. Here, particular attention is given to the exposure-to-biomarker sequence, immune-metabolic remodeling, liquid-biopsy translation, and the reduction of high-dimensional signatures into clinically deployable assays.

Acupuncture therapy shows promise for polycystic ovary syndrome (PCOS), but its molecular mechanisms remain unclear. This study investigates whether acupuncture alleviates PCOS by regulating granulosa cell (GC) ferroptosis via extracellular vesicles (EVs).

Colorectal cancer (CRC) is a leading cause of cancer-related death and is associated with high recurrence rates. Solute carrier family 7 member 5 (SLC7A5), a core transporter that facilitates the transmembrane movement of tryptophan, plays a role in various cancers. However, whether and how SLC7A5 promotes colorectal liver metastasis (CRLM) through tryptophan metabolism reprogramming and immune remodelling remain unexplored.

BCL6 is a master transcriptional regulator of germinal center (GC) B cells. BCL6 is frequently translocated at the major translocation cluster (MTC) within intron 1 of the BCL6 locus, a hotspot commonly rearranged in diffuse large B cell lymphomas (DLBCLs). BCL6 amplifications are associated with therapeutic resistance and poor survival outcomes in hematological and solid cancers. However the mechanisms suppressing genome instability at the BCL6-MTC preventing BCL6 rearragements remain unclear. Here, transcriptome analysis and genome-wide mapping of histone H3 lysine 4 trimethylation (H3K4me3) in hydroxyurea (HU)-treated Raji cells (a Burkitt's lymphoma model) revealed the induced expression of MBD1, encoding the DNA CpG methylation-binding protein. Functional studies using shRNA silencing and ectopic overexpression demonstrated that MBD1 suppresses BCL6 transcription whose promoter harbors conserved CpG methylation sites, suggesting a DNA methylation-dependent regulation of BCL6 trasncription by MBD1. Conversely, BCL6 repressed MBD1 expression by binding to its promoter. MBD1-depleted Raji cells exhibited increased genomic instability at the BCL6-MTC upon HU treatment, heightened sensitivity to DNA replication inhibitors (HU, gemcitabine, and etoposide), and reduced tumorigenicity in xenograft mouse models. We propose that MBD1 prevents genomic instability at the BCL6-MTC to suppress DLBCL formation. Moreover, MBD1 promotes genomic stability and cell viability during DNA replication stress. MBD1 thus represents a potential therapeutic target for cancers exhibiting resistance to chemotherapies targeting DNA replication.

Cervical cancer remains a leading cause of cancer-related morbidity and mortality among women worldwide. Although genomic alterations in oncogenic signaling pathways have been implicated in cervical carcinogenesis, the functional impact of recurrent driver mutations remains incompletely understood. Whole-exome sequencing was performed on paired tumor and matched non-tumor tissues from 61 patients to identify recurrent somatic alterations. Functional significance was subsequently evaluated using cervical cancer cell models through proliferation, invasion, apoptosis, and signaling pathway analyses. Tumorigenic potential was further assessed using a xenograft mouse model. Genomic profiling identified PIK3CA as one of the most frequently mutated genes in cervical cancer. Functional analyses demonstrated that PIK3CA E545K mutation (PIK3CA-E545K-MUT) significantly enhanced tumor cell proliferation and invasive capacity while suppressing apoptosis. Mechanistically, these effects were associated with sustained activation of the AKT/mTOR signaling pathway, as evidenced by increased phosphorylation of key downstream effectors. Consistently, in vivo xenograft experiments confirmed that PIK3CA-E545K-MUT-driven signaling activation promoted tumor growth. Our findings establish a functional and mechanistic link between recurrent PIK3CA-E545K-MUT and aggressive tumor behavior in cervical cancer via AKT/mTOR pathway activation. These results provide experimental support for targeting the PI3K/AKT/mTOR axis as a potential therapeutic strategy in cervical cancer.

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, characterized by high invasiveness, poor prognosis, and limited therapeutic options. Cancer-associated fibroblasts (CAFs), as a core component of the tumor microenvironment (TME), have been shown to promote the malignant progression of NSCLC, but the specific regulatory mechanisms remain incompletely understood. This study aims to investigate the role of CAFs and their metabolic products, particularly lactate, in the progression of NSCLC. CAFs and normal fibroblasts (NFs) were cultured, and the conditioned media (CM) were collected and used to treat NSCLC cells. Cell proliferation was assessed using CCK-8 and EdU assays, while cell migration was evaluated through transwell assays. The expression of E-cadherin and N-cadherin was detected by immunofluorescence (IF). Additionally, lactate levels, gene expression, and lactylation levels were assessed using a lactate detection kit, RT-qPCR, Western blot (WB), and chromatin immunoprecipitation (ChIP). The CM from CAFs enhanced the proliferation, migration, and epithelial-mesenchymal transition (EMT) of NSCLC cells. Our experiments revealed that the metabolites from CAFs, particularly lactate, had a promoting effect on NSCLC. In lactate-treated NSCLC cells, the expression levels of stemness genes were significantly upregulated, accompanied by increased lactylation levels of H3K18. In in vivo experiments, tumors from the lactate treatment group exhibited higher growth rates and increased expression of stemness genes. Furthermore, human NSCLC tumor tissues showed significant upregulation of stemness genes. This study demonstrates that lactate derived from CAFs promotes the expression of stemness genes by mediating H3K18 lactylation in the promoters of these genes in NSCLC cells, thereby accelerating the malignant phenotype formation of NSCLC cells. These findings provide new insights into the role of CAFs in the TME and identify potential therapeutic targets for NSCLC.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design kinase inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 determined co-crystal structures, including a structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazoline-based inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure shows the molecular basis for targeting solvent-front mutations across oncogenic kinases.

Pancreatic acinar cell carcinoma (ACC) is a rare and aggressive malignancy whose molecular basis remains poorly understood. N6-methyladenosine (m⁶A) RNA modification, mediated particularly through methyltransferase 3 (METTL3), has emerged as a critical regulator in various cancers. Here, we investigated the role of METTL3-mediated RNA methylation in ACC development and progression. We used transgenic mouse models overexpressing Mettl3 and SV40 large T antigen under the pancreatic elastase I promoter. Comprehensive analyses included m⁶A-methylated RNA immunoprecipitation sequencing (MeRIP-seq), single-cell RNA sequencing (scRNA-seq), functional studies using the METTL3 inhibitor STM2457, and S-adenosylmethionine (SAM)-binding domain deletion mutants to assess functional requirements. Mettl3 overexpression significantly accelerated ACC development and increased tumor aggressiveness. The SAM-binding domain was essential for tumor formation, as deletion mutants failed to promote carcinogenesis. MeRIP-seq revealed preferential methylation of cell cycle and DNA replication genes in Mettl3-overexpressing tumors. scRNA-seq analysis demonstrated enhanced malignancy signatures, including epithelial-to-mesenchymal transition and transforming growth factor-β signaling. METTL3 also promoted PRSS1-mediated signaling from ACC cells to inflammatory cancer-associated fibroblasts, creating a feed-forward loop involving IGF1 that amplifies tumor growth. Conditional Mettl3 deletion induced rapid tumor apoptosis. Pharmacological inhibition with STM2457 similarly triggered caspase-3/7-dependent apoptosis in pancreatic tumors. METTL3-mediated RNA methylation drives ACC pathogenesis through tumor-intrinsic cell cycle regulation and tumor-extrinsic stromal interactions. These findings establish METTL3 as a promising therapeutic target and provide mechanistic insights supporting the clinical development of METTL3 inhibitors for ACC treatment.

Cancer metabolism is characterized by profound reprogramming, yet the mechanisms enabling rapid and precise adaptation remain incompletely understood. This review establishes post-translational modifications (PTMs) as the central processing unit of oncogenic metabolic reprogramming. PTMs execute a conserved three-tiered regulatory logic: they interpret oncogenic and environmental signals, command metabolic flux, and cement malignant phenotypes through epigenetic and feedback mechanisms. We systematically demonstrate how this PTM-driven logic governs key pillars of cancer metabolism-glucose, lipid, amino acid, and nucleotide utilization-and extends its command to critical cell fate execution programs, including mitochondrial dynamics, autophagy, and ferroptosis. Furthermore, we delineate how PTMs act as master regulators of immunometabolic reprogramming within the tumor microenvironment (TME), directly linking tumor metabolism to T cell exhaustion, myeloid cell polarization, and immune evasion. By integrating recent advances on the determinants and crosstalk of PTM networks, we describe how metabolic plasticity and heterogeneity are encoded at the PTM level, with metabolic gradients shaping distinct "PTM geographies" within tumors. Finally, we translate these insights into clinical prospects, highlighting PTM-based biomarkers, PTM-targeted drugs and emerging therapeutic strategies, including targeted protein degradation, PTM-targeted vaccines and dietary interventions. Deciphering this PTM-encoded program reveals a new landscape of therapeutic vulnerabilities, shifting the paradigm toward rationally targeting the fundamental computational logic that sustains tumors.