Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor with a poor prognosis. Magnetic resonance imaging (MRI) is widely used for the clinical diagnosis and prognostic evaluation of GBM. This study aimed to investigate the relationship between MRI semantic features and overall survival, and to explore the underlying biological mechanisms by transcriptomic analysis. In this study, we reviewed the MRI images of 171 patients with GBM from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases and evaluated twelve MRI semantic features. Cox regression model and Kaplan-Meier survival curve were used to assess the prognostic value of the imaging features. Additionally, we investigated the relationship between imaging features and gene expression using differential gene expression and enrichment analysis in the cohort of 68 tumor samples with RNA-seq data. 171patients with GBM were included in the imaging-prognostic cohort (median age was 60.0 years and 59.6% were male). In the multivariate analyses, age (HR: 1.04, 95% CI: 1.03-1.06, P < 0.001), ependymal extension (HR:1.88, 95% CI:1.32-2.69, P < 0.001), contrast-enhancing tumor (CET) crossing midline (HR:2.38, 95% CI:1.16-4.91, P = 0.018) were significantly associated with shorter overall survival (OS). Gene set enrichment analysis (GSEA) showed that these features were significantly associated with pathways involved in inflammatory responses and tumor invasiveness, such as TNF-α signaling via NF-κB and epithelial-to-mesenchymal transition. Our study demonstrated that MRI semantic features, including ependymal extension and CET crossing the midline, can serve as prognostic indicators for patients with GBM. Additionally, several selected MRI features were found to be associated with specific biological pathways, potentially informing treatment decisions based on these distinctive semantic characteristics of GBM.

Claudin-low breast cancers (BCs), representing approximately 1.5-14% of all BCs, are characterized by high aggressiveness, enriched cancer stem cell (CSC) population, and poor prognosis. Despite the established role of Notch signaling in mammary gland development and BC progression, its status in claudin-low BCs remains inadequately explored. In this study, Notch pathway activation was evaluated in BC cell lines and 107 patient samples. Claudin-low subtype exhibited elevated Notch activity. Notch1 was observed to be the predominant receptor in the above subtype, whereas Notch3 was predominant in the claudin-high cancers. Notch1 and HES1 expression showed a significant inverse correlation with claudins 3, 4, and 7, and were positively associated with aggressive tumor features including high Ki67 index, higher grade, and increased metastasis. Immunohistochemical analysis further confirmed a correlation between nuclear Notch1 (N1ICD) expression and claudin-low status, supporting its potential as a biomarker for identification of aggressive BC. Combined treatment with celecoxib (10 µM) and doxorubicin (1 µM) in claudin-low cells not only significantly inhibited Notch signaling and claudin expression, but also suppressed viability, proliferation, migration, and BCSC populations. Since Notch signalling may be an essential factor in these latter events, our findings suggest that Notch1/N1ICD can serve as therapeutic targets for the better management of claudin-low BCs. However, validation of the same requires detailed functional studies involving modulation of each type of Notch receptor or other players involved in Notch signaling using more robust approaches.

Colorectal cancer (CRC) progression is heavily influenced by the tumor microenvironment (TME), where cancer-associated fibroblasts (CAFs) are key players. However, the heterogeneity, plasticity, and functional roles of CAFs in CRC remain poorly understood.

This article highlights selected cutaneous mesenchymal tumors, emphasizing histopathology, immunophenotype, and molecular alterations. It outlines diagnostic pitfalls, distinguishing features, and clinical behavior of indolent and malignant lesions. Awareness ensures accurate and appropriate treatment, and prevents overtreating benign mimics.

Refinements in histologic criteria, staging systems (American Joint Committee on Cancer 8th edition, Brigham and Women's Hospital), clinical guidelines (National Comprehensive Cancer Network [NCCN]), and molecular tools like gene expression profiling have enhanced the precision of cutaneous squamous cell carcinoma diagnosis and treatment. In Merkel cell carcinoma, recent updates in viral pathogenesis, immunohistochemistry, and emerging biomarkers have aided in better diagnostics. As immunotherapies and precision oncology evolve, dermatopathologists remain essential in guiding patient-specific management strategies for both cutaneous squamous cell carcinoma and Merkel cell carcinoma.

Cutaneous adnexal tumors recapitulate hair follicles, sweat glands, and/or sebaceous glands. These tumors range from benign to malignant and might herald an underlying inherited tumor syndrome. Accurate classification of adnexal tumors is thus critical but can be challenging due to many knowledge gaps in this area. Recent advances have dramatically improved our understanding and diagnosis of adnexal tumors. Here, we review several recently described adnexal carcinomas and summarize new molecular drivers reported in previously established tumor entities. We highlight morphologic, immunohistochemical, and molecular clues helpful for diagnosis of these adnexal tumors.

Vulvar squamous cell carcinoma and its precursors are heterogeneous and classified into 3 biologically distinct subgroups: human papillomavirus (HPV)-associated, HPV-independent TP53-mutated, and HPV-independent TP53-wild type. Although nomenclature is established for HPV-associated high-grade squamous intraepithelial lesion and TP53-mutated differentiated vulvar intraepithelial neoplasia lesions, terminology for precursors in the TP53-wild-type subgroup is evolving. Accurate classification is essential, as prognosis, progression risk, and recurrence rates differ among subgroups. Diagnosis relies on integrated assessment of clinical presentation, histopathology, and immunophenotype, particularly p16 and p53 expression.

In the past 2 decades, several molecular methods have been developed as an adjunct for the assessment of melanocytic neoplasms. Some tests can assist in the diagnostic workup of neoplasms with ambiguous histopathologic findings. Others can optimize the selection of patients for targeted therapy. Some tests also aim to provide prognostic information. Scenarios when ordering these tests may be appropriate and helpful are discussed in this article as well as pitfalls in the interpretation of test results. Due to the inherent limitations in sensitivity and specificity of various tests, correlation with the histopathologic findings is paramount.

Metabolic reprogramming is a hallmark of cancer, while tricarboxylic acid cycle is increasingly recognized as a multifaceted hub driving tumor metabolism and progression. Integrated analysis of solute carrier (SLC) transporters revealed consistent down-regulation of SLC13A2 in hepatocellular carcinoma (HCC) cells and liver tissues from human patients and mouse models. Adeno-associated virus-mediated liver-specific knockout or overexpression of SLC13A2 (SLC13A2-OE) promoted or ameliorated HCC progression, indicating its protective role. SLC13A2 inhibited HCC proliferation by decreasing mitochondrial function via suppressed glycolysis, respiration, and adenosine 5'-triphosphate production. Flux analysis showed that SLC13A2 imported citrate to generate acetyl-coenzyme A for pyruvate kinase isozyme type M2 acetylation, triggering its degradation. Reduced pyruvate kinase activity limited pyruvate supply, impairing amino acid synthesis and nucleotide metabolism. Moreover, SLC13A2-imported citrate induced intracellular protein acetylation, particularly histone proteins, which provided an epigenetic basis for transcriptional regulation and contributed to tumor suppression. Thus, SLC13A2 perturbs metabolic and transcriptional programs to suppress tumor growth, highlighting potential drug targets for HCC therapy.

Tumor-derived exosomes play critical roles in pancreatic ductal adenocarcinoma (PDAC) progression by mediating intercellular communication within the tumor microenvironment. This study identifies the long non-coding RNA PLBD1-AS1 as a functional oncogenic lncRNA enriched in PDAC exosomes. We demonstrate that PLBD1-AS1 promotes tumor cell proliferation, migration, and invasion by interacting with the glycolytic enzyme ALDOA and enhancing glycolytic flux. Furthermore, tumor exosomes deliver PLBD1-AS1 to pancreatic stellate cells (PSC), augmenting their glycolysis and facilitating their activation into cancer-associated fibroblasts, thereby shaping a pro-tumorigenic microenvironment. To target it, we developed an engineered exosome system modified with the tumor-penetrating peptide iRGD for specific delivery of siPLBD1-AS1 to both tumor and stromal cells. The resulting iRGD-exo-siPLBD1-AS1 construct demonstrated enhanced cellular uptake and effectively suppressed PLBD1-AS1 expression, inhibited glycolysis, impaired PSC activation, and significantly attenuated tumor growth. Our findings reveal a novel mechanism of exosome-mediated metabolic crosstalk in PDAC and establish a promising RNAi-based therapeutic strategy targeting this lethal malignancy.

Bladder cancer remains a significant therapeutic challenge due to its marked heterogeneity and capacity for immune evasion. Here, we employ spatial metabolomics and spatial transcriptomics to systematically characterize and visualize the metabolic and transcriptional landscapes of bladder cancer. Our findings identify distinct metabolic and transcriptional profiles across different tumor regions, highlighting heterogeneity and immune-associated metabolic reprogramming in BLCA. Further investigation identifies zinc finger protein 36 (ZFP36) as a potential immunotherapeutic target. Utilizing Zfp36 whole-body knockout and T cell-specific Zfp36 conditional knockout mice, we validated that Zfp36 knockout decreases the activation threshold for T cells and increases T cell infiltration in tumors. Moreover, we found that elevated ZFP36 expression is dramatically linked to worse patient outcomes. Mechanistically, ZFP36 facilitates mRNA degradation of key immune regulators, including C1QBP, thereby inhibiting T cell activation and cytotoxicity. Notably, combining Zfp36 knockout with anti-PD-1 therapy produced synergistic antitumor effects, suggesting that ZFP36 inhibition could be a promising therapeutic strategy. This integrated multiomics approach collectively uncovers immune-metabolic regulatory pathways in BLCA and points to critical molecular targets for immunotherapy.

Ewing sarcoma is driven by chromosomal translocations that fuse a FET RNA-binding protein to an ETS transcription factor, most commonly generating the EWS-FLI1 fusion oncoprotein. EWS-FLI1 engages GGAA microsatellite repeats to form de novo enhancers that activate oncogenic transcriptional programs essential for tumorigenesis. In addition to this truncal driver, recurrent loss-of-function alterations in the cohesin subunit STAG2 occur in approximately 10 to 15% of Ewing sarcomas and are associated with adverse clinical outcomes. However, how STAG2 loss reshapes EWS-FLI1 chromatin engagement and transcriptional output remains poorly understood. Here, using genetic STAG2 loss-of-function models combined with integrative multiomic profiling, we demonstrate that STAG2-cohesin deficiency reprograms the EWS-FLI1 chromatin landscape by altering its binding at GGAA-microsatellite enhancers. Despite increased EWS-FLI1 protein abundance, STAG2 loss eliminates over 40% of EWS-FLI1 binding sites, predominantly at enhancers containing short (1-4) GGAA repeats, while concurrently increasing binding at multimeric enhancers with ≥5 GGAA-repeat motifs. These reprogrammed sites show changes in both chromatin accessibility and H3K27ac, leading to selective amplification of EWS-FLI1 activity at multimeric microsatellite enhancers. By integrating Hi-C chromatin interaction maps with altered EWS-FLI1 occupancy, we define distinct monomeric and multimeric GGAA enhancer-driven transcriptional gene signatures and demonstrate that STAG2 loss selectively augments the multimeric transcriptional program. Consistently, the long GGAA microsatellite-activated gene signature is enriched in patient tumors with aggressive clinical features and deleterious STAG2 alterations. Together, these findings reveal that STAG2 loss reprograms, rather than globally attenuates, EWS-FLI1 function, amplifying a high-risk oncogenic transcriptional state in Ewing sarcoma.

Risk-reducing bilateral salpingo-oophorectomy is recommended to substantially lower ovarian cancer risk in women carrying BRCA1 or BRCA2 pathogenic variant (PV). The use of hormone replacement therapy (HRT) after risk-reducing bilateral oophorectomy (RRBO), although generally recommended, remains debated due to concerns about its possible role in breast cancer (BC) risk.

Androgen deprivation therapy (ADT) remains the standard treatment for advanced prostate cancer (PCa); however, most patients ultimately progress to lethal castration-resistant PCa (CRPC). Emerging evidence implicates RNA N⁶-methyladenosine (m⁶A) modification as a key regulator of cancer biology, yet its role in CRPC remains poorly understood. As a critical adaptor in the m⁶A methyltransferase complex, RNA-binding motif protein 15 (RBM15) directs m⁶A deposition to specific mRNA targets. Here, we identified RBM15 as the key methyltransferase member significantly upregulated in CRPC tissues and strongly correlated with poor patient survival. Functionally, RBM15 overexpression reduces PCa cell sensitivity to enzalutamide, whereas its knockdown suppresses tumor growth and invasion. Mechanistically, RBM15 is an androgen-responsive protein whose expression increases upon chronic androgen deprivation. It catalyzes m⁶A methylation at position A1384 of damaged DNA binding protein 1 (DDB1) mRNA, leading to YTHDF2-dependent transcript decay and reduced DDB1 protein levels. Lower DDB1 impairs K48-linked polyubiquitination of the androgen receptor (AR), thereby stabilizing AR and amplifying AR signaling. Importantly, AR transcriptionally activates RBM15, forming a feed-forward loop that drives CRPC progression. Collectively, our findings establish RBM15 as a central epitranscriptomic driver of CRPC and identify the RBM15-DDB1-AR axis as a promising therapeutic target. Dual inhibition of RBM15 and AR may offer a novel strategy to overcome treatment resistance in advanced PCa.

Members of the Lysine MethylTransferase 2 (KMT2) family are often abnormally expressed and mutated in many cancers. Similarly, several mutations listed in cancer databases map to key functional regions of KMT2 regulatory subunits, such as WD repeat domain 5 (WDR5), Retinoblastoma binding protein 5 (RbBP5), absent-small-homeotic-2-like (ASH2L), and DumPY-30 (DPY-30). In this study, we report the systematic characterization of cancer-associated mutations that map to regions important for the WDR5/RbBP5/ASH2L/DPY-30 (WRAD) complex formation. Both binding and thermal stability assays show that several cancer-related mutations do not affect ASH2L binding to DPY-30 or RbBP5. A subset of gain-of-function mutants highlights the role of long-range networks of interactions underlying RbBP5 binding by ASH2L. Parallel analysis of RbBP5 mutations shows additional variants that weaken its interactions with WDR5. Finally, systematic mapping of RbBP5 residues interacting with WDR5 defines the optimal WDR5-binding motif and shows that introducing hydrophobic residues beyond the central VDV sequence increases binding affinity. Overall, these findings reveal surprising gain-of-function mutations in ASH2L and provide a framework for targeting this epigenetic hub therapeutically.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, yet its genetic etiology remains poorly understood. In this study, we described a family from the Shanghai General Hospital Osteosarcoma (SGH-OS) cohort in which two siblings developed osteosarcoma as their first primary malignancy, and we investigated the germline and somatic genetic basis underlying this familial presentation.

Telomerase is active in the majority of high-risk neuroblastomas, a pediatric tumor associated with poor patient outcomes. In other cancer types, resistance to immune checkpoint blockade was overcome by induction of telomere dysfunction using the telomerase substrate precursor 6-thio-2'-deoxyguanosine (6-thio-dG). Here, we explored whether induction of telomere dysfunction improves the anti-tumor efficacy of immune checkpoint inhibition in neuroblastoma. 6-thio-dG treatment induced the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and programmed cell death ligand-1 (PD-L1) expression in murine neuroblastoma cells in vitro. In a MYCN;ALKF1174L-driven transgenic neuroblastoma mouse model, 6-thio-dG treatment delayed tumor growth and prolonged survival. Treatment with anti-PD-L1 also led to growth delay and improved survival, which occurred; however, only after an initial lag phase. Combination with anti-PD-L1 improved the anti-tumor effects of 6-thio-dG and overcame the initial lag phase of anti-PD-L1 treatment. Mechanistically, 6-thio-dG combined with anti-PD-L1 treatment induced cGAS and PD-L1 expression and promoted immune cell infiltration in the tumors. Our findings suggest that 6-thio-dG treatment activates the cGAS-STING pathway in neuroblastoma and that induction of telomere dysfunction in combination with immune checkpoint blockade boosts intratumoral immune cell infiltration and improves survival in a high-risk neuroblastoma mouse model.

Supernumerary centrosomes are a hallmark of cancer. To maintain viability, cancer cells cluster these centrosomes during mitosis, enabling bipolar division similar to that of normal cells. Disruption of this centrosome clustering leads to multipolar anaphase and apoptosis (anaphase catastrophe), which selectively eliminates cancer cells harboring supernumerary centrosomes. In this context, because the motor protein KIFC1 contributes to centrosome clustering, we investigated whether targeting of this mechanism through KIFC1 inhibition could be exploited in small-cell lung cancer (SCLC), an aggressive malignancy with limited treatment options and poor prognosis. Through in silico and in vitro analyses, as well as IHC of clinical samples, we found that KIFC1 is overexpressed and that centrosome amplification occurs more frequently in SCLC compared with normal tissues and other cancer types. Pharmacological and genetic inhibition of KIFC1 disrupted the clustering of supernumerary centrosomes, triggered multipolar mitosis, and exerted antineoplastic effects in SCLC cells, with minimal effects on noncancerous cells. These findings were validated and extended in vivo using SCLC xenograft models. Finally, cotargeting KIFC1 and the centrosome duplication regulator PLK4 further enhanced growth suppression in SCLC cells. Together, these results suggest that disrupting centrosome clustering and triggering anaphase catastrophe via KIFC1 inhibition may represent a promising therapeutic strategy for SCLC.

The bone marrow workshop (session 3), held at the 22nd Meeting of the European Association for Hematopathology/Society of Hematopathology in Dubrovnik, was dedicated to myeloid/lymphoid precursor cell neoplasms and mixed-phenotype acute leukemias (MPALs). We hereby report the clinicopathologic, immunophenotypic, and genetic features of the submitted cases.

The overall survival rate of acute myeloid leukemia (AML) remains less than 30%. Metabolic reprogramming of leukemia cells, such as the Warburg effect, enables them to adapt to the microenvironment and thereby develop. Elucidating the landscape of lactate regulation in AML helps clarify the pathogenesis from the perspective of metabolic reprogramming and identify possibilities for optimizing current treatment modalities.