Cancer originates from the uncontrolled proliferation of normal cells. Previous studies have demonstrated that CDC25B, a cell cycle-regulating phosphatase, is overexpressed in various tumors, including hepatocellular carcinoma, and its expression level may serve as a prognostic biomarker. The present study investigated the upstream miRNA regulators of CDC25B and demonstrated that their interactions can inhibit hepatocellular carcinoma progression. Here, stable hepatocellular carcinoma cell lines overexpressing or knocking down CDC25B were established using lentiviral vectors. The effects of CDC25B expression on the invasive phenotype of hepatocellular carcinoma cells were analyzed using plate cloning, scratch assays, and Transwell assays, and a subcutaneous tumor xenograft model in mice was established to evaluate the impact of CDC25B on tumor growth in vivo. Furthermore, dual-luciferase reporter assays were used to validate the targeted regulatory relationship between miR-200a-3p and CDC25B, while miR-200a-3p mimics and inhibitors were employed to elucidate the specific downstream mechanisms. We found that high expression of CDC25B significantly enhanced the epithelial-mesenchymal transition process, thereby accelerating the proliferation, invasion, and migration of hepatocellular carcinoma cells, whereas CDC25B knockdown exerted the opposite effects. In vivo tumorigenicity experiments in nude mice confirmed that overexpression of CDC25B promoted tumor growth. In addition, the dual-luciferase reporter assay confirmed that miR-200a-3p specifically targets and downregulates CDC25B expression, thereby inhibiting hepatocellular carcinoma progression.

Meningiomas exhibit marked biological heterogeneity that is not fully captured by current histopathological grading. Increasing evidence suggests that mitochondrial metabolism contributes to tumor aggressiveness; however, the molecular mechanisms regulating mitochondrial function in meningiomas remain poorly defined. Here, we investigated the role of mitochondrial transcription factor A (TFAM)-driven mitochondrial biogenesis and translation in meningioma progression. We performed integrative transcriptomic, immunohistochemical, and mitochondrial DNA analyses in a well-characterized cohort of 91 meningiomas, comprising World Health Organization grade 1 (G1) and grade 2 (G2) tumors with long-term clinical follow-up. RNA sequencing identified enrichment for mitochondrial metabolic pathways, including oxidative phosphorylation and ATP metabolism, that was preferentially activated in G2 meningiomas. TFAM and its upstream regulator PGC1α were significantly upregulated at both mRNA and protein levels in G2 tumors and exhibited a positive correlation, consistent with enhanced mitochondrial biogenesis. Although mitochondrial DNA copy number did not differ significantly between grades, G2 meningiomas showed a trend toward increased mitochondrial mass. Notably, G2 meningiomas demonstrated marked enrichment of mitoribosomal genes, including MRPL15, MRPL35, MRPL42 and MRPS22, whose expression correlated positively with TFAM and PGC1α expression levels. Network analysis identified TFAM as a central hub linking mitochondrial biogenesis, translation, and metabolic pathway activation. These findings were independently validated using a publicly available meningioma transcriptomic dataset. Together, our results reveal a TFAM-centered mitochondrial regulatory program that integrates mitochondrial biogenesis, translational capacity, and oxidative metabolism in higher-grade meningiomas. This mitochondrial translational axis represents a previously unrecognized mechanism underlying meningioma progression and highlights potential metabolic vulnerabilities for therapeutic intervention.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. Cigarette smoke extract (CSE) is a major environmental factor driving NSCLC progression, yet the underlying molecular mechanisms remain incompletely understood. Protein arginine methyltransferase 6 (PRMT6) is implicated in various malignancies, including NSCLC, and epithelial-mesenchymal transition (EMT) contributes to metastasis and poor prognosis in this disease. However, the role of PRMT6 in CSE-induced NSCLC progression has not been elucidated.

Cancer immunotherapy has shown significant promise in certain patient populations, but further advancements are needed to extend its benefits to a wider range of patients. Clustered regularly interspaced short palindromic repeats (CRISPR)-based editing has rapidly evolved in recent years, enabling its transition into direct therapeutic applications. This review summarizes recent progress in applying CRISPR systems in vivo for cancer immunotherapy, focusing on approaches that target cancer cells and the tumor microenvironment, as well as those that directly engineer immune cell populations themselves. Novel CRISPR editing platforms and strategies enabling multiplexed editing have also recently demonstrated promising impacts on driving antitumor immunity, however, the platforms investigated are still in the early stages and further investigation will be needed to robustly assess the potential for clinical translation. Future work can expand the array of therapeutic targets by incorporating data from functional genomics and must also carefully evaluate both editing modalities and delivery systems to optimize efficacy, safety, and scalability.

Pediatric testicular and ovarian germ cell tumors generally have favorable outcomes, but a subset of patients experience relapse, progression, or persistent disease. Conventional risk assessment is based primarily on stage, histology, primary site, serum tumor markers, and treatment response; the incremental prognostic value of genomic profiling remains uncertain.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis and limited treatment options. Disulfidptosis, a novel cell death pathway driven by disulfide bond accumulation, has emerged as a potential mechanism in cancer biology; however, its role in ICC remains unclear.

Lung squamous cell carcinoma (LUSC) represents a predominant subtype of non-small cell lung cancer (NSCLC) with scarce effective targeted therapeutic options, rendering immune checkpoint inhibitor (ICI)-based regimens the standard first-line treatment for advanced-stage disease. Fibroblast growth factor receptor 1 (FGFR1) copy number (CN) gain is a prevalent genomic aberration in LUSC; nevertheless, the correlation between FGFR1 CN gain and ICI therapeutic efficacy has not yet been clarified. This retrospective single-center study aimed to explore the predictive value of FGFR1 CN gain in advanced LUSC patients receiving first-line ICI monotherapy or combination regimens.

Steroid hormone receptors are traditionally described through models derived from simplified experimental conditions that do not fully recapitulate the physiological environment. In this review, we propose an integrated physiological framework for understanding steroid receptor function, in which chromatin organization, mechanotransduction, receptor network plasticity, and dynamic nuclear organization are recognized as fundamental components of hormone signaling rather than secondary regulatory layers. We highlight how steroid receptor signaling in breast cancer emerges from the coordinated integration of hormonal, chromatin, and mechanical cues, rather than from isolated ligand-driven events. In vivo, hormone responses occur within a complex endocrine milieu characterized by fluctuating hormone concentrations, multiple receptor interactions, and continuous communication with the chromatin landscape. Emerging evidence further indicates that biomolecular condensates and dynamic receptor assemblies contribute to the spatial and temporal coordination of transcriptional programs. By integrating advances in nuclear receptor biology, chromatin regulation, and mechanobiology, we argue that many mechanisms historically classified as "noncanonical" are more appropriately viewed as integral components of physiological steroid receptor function. This integrated perspective provides a broader framework for understanding breast cancer biology, disease progression, and therapeutic response.

Chronic myeloid leukemia (CML) with megakaryoblastic blast crisis (MKBC) as the initial manifestation is extremely rare, accounting for less than 3% of all CML cases. Philadelphia chromosome-positive acute myeloid leukemia, FAB M7 subtype (Ph+ AML-M7), is also known as Philadelphia chromosome-positive acute megakaryoblastic leukemia (Ph+ AMKL), representing a distinct and prognostically unfavorable category of AML. Morphologically and immunophenotypically, these two entities are nearly identical, posing significant diagnostic challenges. We describe a novel case of Ph+ leukemia with MKBC differentiation that appears most consistent with CML in blast phase (BP). Following treatment with a tyrosine kinase inhibitor (TKI) combined with induction and consolidation chemotherapy, the patient achieved complete remission (CR). Although hematopoietic stem cell transplantation (HSCT) was declined due to economic constraints, the patient has maintained deep molecular remission(MR5, BCR::ABL1IS ≤ 0.001%)for 35 months to date. Through a systematic review of existing literature, this article elucidates key discriminative features between the two conditions and proposes a practical diagnostic and therapeutic framework to guide clinical decision-making.

Lineage switch (LS), defined as a change in leukemic lineage during the disease course, is a rare but clinically significant event in acute leukemia and is typically associated with poor prognosis. Although LS has been increasingly reported following targeted immunotherapies, the clonal mechanisms underlying this phenomenon remain incompletely understood, particularly in cases without KMT2A rearrangement. We report a case of LS from B-precursor acute lymphoblastic leukemia (BCP-ALL) to acute myeloid leukemia (AML) following treatment with the CD22-targeted antibody-drug conjugate inotuzumab ozogamicin. To elucidate the clonal architecture underlying LS, targeted next-generation sequencing was performed on bone marrow samples obtained at multiple time points throughout the disease course. Genomic analysis demonstrated that the lymphoid and myeloid disease phases shared ancestral genetic alterations but displayed distinct mutational profiles. At the time of LS, TP53 and SMC1A mutations newly emerged, whereas only a subset of mutations detected at ALL relapse was retained. These findings suggest that the AML phase most likely resulted from the selective expansion of a genetically distinct subclone derived from a common progenitor, rather than the direct transdifferentiation of the dominant ALL clone, consistent with immunotherapy-driven clonal selection. Longitudinal genomic profiling revealed stepwise clonal evolution during disease progression, supporting a model of immunotherapy-driven clonal selection leading to LS. This case provides molecular evidence suggesting that immune-targeted therapy can promote expansion of minor pre-existing subclones with alternative lineage potential within a common progenitor even in non-KMT2A-rearranged leukemia. Our findings highlight the importance of comprehensive genomic monitoring during immunotherapy to identify therapy-resistant subclones and better understand mechanisms of lineage plasticity in acute leukemia.

Nucleophosmin 1-mutated (NPM1mt) acute myeloid leukemia (AML) is associated with a relatively favorable prognosis though long-term outcomes remain suboptimal without clear predictors identified by therapy.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed precision oncology by exploiting synthetic lethality in homologous recombination (HR)-deficient cancers, with multiple FDA-approved agents targeting BRCA1/2-mutant tumors. Despite initial efficacy, resistance inevitably emerges, limiting long-term clinical benefit. This review synthesizes emerging mechanistic insights into PARPi response and resistance. Recent evidence reframes PARP inhibition cytotoxicity through a transcription-replication conflict model and identifies single-stranded DNA gaps as the primary lethal lesion in HR-deficient cells, rather than double-strand breaks. These findings suggest that resistance reflects restoration of replication gap suppression or resolution of transcription-replication stress. We further highlight DNA ligase III as a collateral vulnerability in 53BP1-deficient resistant tumors, and discuss proteolysis-targeting chimera (PROTAC)-based PARP1 degraders as a strategy to overcome resistance and induce alternative cell death pathways. Established resistance mechanisms-including BRCA1/2 reversion mutations, shieldin complex loss, RAD51 hyperactivation, and pharmacokinetic alterations-are reconsidered within this updated framework. Combination strategies with ATR inhibitors show promising clinical activity in PARPi-resistant HR-deficient ovarian cancer. Finally, we propose an integrated biomarker framework combining HRD scar assays, functional RAD51 foci analysis, replication gap profiling, and circulating tumor DNA (ctDNA) monitoring to enable dynamic resistance tracking.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Approximately 15% of localized and 5% of metastatic cases exhibit mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). While immune checkpoint inhibitors (ICIs) have revolutionized the first-line treatment for this subgroup, 15%-46% of patients experience primary resistance, and a subset of responders eventually acquires resistance. This review synthesizes the multifaceted mechanisms underlying ICI resistance in dMMR/MSI-H CRC. We delineate tumor-intrinsic alterations, including defects in the antigen presentation machinery (specifically transporter associated with antigen processing [TAP]1/TAP2 and β2-microglobulin [β2m]), oncogenic signaling via the Wnt/β-catenin and JAK/STAT pathways, and epigenetic remodeling involving ARID1A. Furthermore, we explore the role of the immunosuppressive tumor microenvironment (TME), characterized by T-cell exclusion and myeloid-derived suppressor cell (MDSC) accumulation. To address these barriers, we evaluate the clinical potential of third-generation ICIs targeting lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and TIGIT, as well as emerging biomarker strategies such as gut microbiome modulation and circulating tumor DNA (ctDNA) dynamics. By integrating these mechanistic insights with novel therapeutic approaches, including bispecific antibodies (BsAbs) and adoptive cell transfer, this review aims to provide a roadmap for overcoming resistance and advancing precision immunotherapy in dMMR/MSI-H CRC.

BRAFV600-mutant metastatic colorectal cancer comprises a biologically distinct and clinically aggressive subset of metastatic colorectal cancer. Early attempts to apply single-agent BRAFV600 inhibition failed because of rapid acquired resistance and reactivation of mitogen-activated protein kinase signaling. Over the last decade, rational combinations (BRAF inhibitors and epidermal growth factor receptor inhibitors with or without mitogen-activated protein kinase kinase inhibitors) have become the standard of care in the refractory setting and are now being evaluated upfront, whereas a wave of next-generation approaches (extracellular signal-regulated kinase and SHP2 inhibitors, receptor tyrosine kinase-targeted agents, and immunotherapy combinations) aims to prevent or overcome resistance. The objective of this comprehensive review was to summarize historic therapeutic approaches, current standards, and the mechanistic rationale and clinical development of next-generation strategies to combat resistance in BRAFV600-mutant metastatic colorectal cancer.

Tumors exhibiting mismatch repair deficiency without detectable germline mutations via standard multigene panel testing are often classified as Lynch-like syndrome. In the present report, we describe the case of a 47-year-old man presenting with synchronous axillary sebaceous carcinoma and colonic medullary carcinoma. Although initial germline multigene panel testing failed to identify pathogenic variants, a high degree of pathological suspicion for Muir-Torre syndrome remained. Immunohistochemistry revealed a concordant loss of MSH2 and MSH6 expression in both the extraocular sebaceous carcinoma and the colonic medullary carcinoma. This identical protein-loss pattern detected across anatomically distinct tumors served as decisive pathological evidence of an underlying germline defect rather than independent biallelic somatic mutations. Consequently, whole-genome sequencing was performed to resolve the discrepancy between the pathological findings and multigene panel testing results, successfully identifying a germline intronic MSH2 variant (NM_000251.3:c.2459-12A>G). Subsequent RNA analysis confirmed aberrant splicing with an 11-bp insertion. In conclusion, the present case illustrates that concordant mismatch repair protein loss across multiple tumors provides compelling morphological evidence to guide pathologists in reconsidering negative panel results and pursuing comprehensive genomic investigation to identify pathogenic intronic variants.

DNA methylation-based classification is a key adjunct to histopathology in CNS tumor diagnostics. Although both fresh-frozen and FFPE tissues are used, the impact of sampling strategy on classifier performance remains insufficiently characterized. We analyzed 179 CNS specimens (162 tumors and 17 controls), including 42 FFPE and 137 fresh-frozen samples with ≥ 50% tumor cellularity. Fresh-frozen cases were stratified into histology-validated and blind sampling groups. Genome-wide DNA methylation profiling was performed using Illumina EPIC/EPIC v2.0 arrays and classified using the DKFZ Brain Tumor Classifier, with independent validation using the NIH Methylscape platform. Results were categorized as confirmed, refined, changed, or unclassified and correlated with histopathological diagnoses. FFPE samples showed high diagnostic yield with minimal unclassified results (2%). Among fresh-frozen specimens, histology-validated samples demonstrated robust classification, whereas blind sampling showed higher discordance and unclassified rates (22%). Discordant results were confined to the blind-sampling group and were most consistent with sampling bias and variable tumor representation rather than technical limitations. Methylation profiling confirmed or refined diagnoses in most cases and led to clinically relevant reclassification in a subset. Classifier performance appeared to be influenced more by sampling strategy rather than preservation method, with histology-guided sampling associated with the most reliable diagnostic outcomes.

Esophageal squamous cell carcinoma (ESCC) features epithelial heterogeneity and an immunosuppressive microenvironment, yet clinically relevant malignant epithelial states remain poorly defined. We integrated four single-cell RNA-sequencing datasets and 10 bulk transcriptomic cohorts totaling 1318 samples, and applied cross-cohort differential expression, survival analysis, and a machine-learning framework of 113 algorithm combinations to screen for malignant epithelial cell-associated biomarkers. GNGT1 was prioritized for its consistent upregulation, prognostic association, and limited prior characterization in ESCC. Across independent cohorts, GNGT1 exhibited favorable diagnostic performance, while high expression correlated with poorer overall survival and more advanced local tumor status. Immune deconvolution consistently linked GNGT1-high tumors to reduced CD8+ T-cell infiltration, lower immune scores, and decreased cytotoxic T-cell markers. Single-cell analyses further associated GNGT1-high epithelial cells with altered epithelial-immune communication involving MIF, prostaglandin, and CXCL signaling, alongside enrichment of epithelial-mesenchymal transition, mTORC1, and proliferative programs; qPCR confirmed elevated GNGT1 expression in ESCC cell lines. This study defines GNGT1 as a marker of an immunosuppressive malignant epithelial state, thereby bridging epithelial heterogeneity with immune remodeling in ESCC. These findings support GNGT1 as a candidate diagnostic, prognostic, and biologically informative biomarker warranting mechanistic and clinical validation.

Lysine β-hydroxybutyrylation (Kbhb) is a metabolite-derived post-translational modification of histone and non-histone proteins that couples β-hydroxybutyrate (BHB) availability to gene expression. Yet the transcription factors that govern the Kbhb substrate program in cancer remain unidentified. Existing studies have cataloged Kbhb-modified substrates or examined individual proteins, without identifying the transcriptional regulators of the program in a defined tumor context. Here, we performed network-based master regulator analysis (MRA), implemented in the viper package, on a molecular signature restricted to experimentally validated Kbhb substrates, across two independent PAM50 Basal-like breast cancer (BLBC) cohorts profiled on orthogonal platforms: TCGA-BRCA (RNA-seq; n = 195 tumor, 113 normal) and METABRIC (microarray; n = 209 tumor, 148 normal). Dataset-specific regulatory networks were inferred with ARACNe-AP and integrated by cross-platform Stouffer meta-analysis. Of 1493 Kbhb substrates, 1322 and 1213 were expressed in the respective cohorts. The analysis identified seven concordant transcriptional master regulators (six activated, one repressed; cross-cohort NES correlation r = 0.64), with CENPA (meta-NES +4.55) and FOXM1 (meta-NES +4.27) as the dominant drivers. These findings nominate a BHB-Kbhb-FOXM1/CENPA axis linking ketone-body metabolism to mitotic transcription, with potentially protumoral implications for ketogenic regimens in BLBC.

Exosomes are small extracellular vesicles that mediate intercellular communication and, in cancer, carry cargo that both reflects the donor tumor cell and influences recipient cells within local and distant microenvironments. Exosomal proteins and microRNAs have been reported individually across many cancer types, but rarely compared on a common basis; in this review, previously reported molecules from eight cancer categories-blood, breast, colon, kidney, liver, lung, prostate, and stomach-were compiled from curated repositories and re-analyzed within a single functional framework. In total, 3643 exosomal proteins (523 hematologic, 3120 solid-tumor) and 627,225 miRNA-target pairs, derived from 350 unique microRNAs, were organized using Gene Ontology, KEGG, and PANTHER annotation. Across cancers, proteins converged on a reproducible core-signaling, transport, cytoskeletal organization, and extracellular interaction-dominated by binding, catalytic, and transporter functions localized to membrane, vesicle, and extracellular compartments. Comparisons between hematologic and solid malignancies revealed both shared cancer-associated functions and context-dependent patterns linked to tissue origin and disease ecology. Together, these findings indicate that integrated protein-and-microRNA profiling offers a useful framework for understanding tumor communication, refining cancer classification, and advancing biomarker discovery, while underscoring that harmonized workflows, independent validation, and mechanistic follow-up remain necessary before descriptive enrichment outputs can support clinically robust applications.

As an important member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, ADAMTS16 participates in various physiological and pathological processes through the regulation of extracellular matrix (ECM) components. This review systematically delineates the expression profiles of ADAMTS16 in different tissues and cell types, as well as its diverse roles in reproductive development, cardiovascular diseases, ocular diseases, skeletal disorders, malignancies, and other pathological conditions, revealing significant differences in its expression patterns and mechanisms of action across various tissues. Cumulatively, current evidence suggests that ADAMTS16 may engage in direct or indirect interactions with ECM constituents to regulate cell proliferation, differentiation, and migration, and may also influence a range of cellular activities via synergistic cooperation with other cytokines.