Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy that is characterised by a pathognomonic t(X;18)(p11.2;q11.2) translocation, which produces the fusion oncogene named SS18::SSX. Despite recent advancements in our understanding of synovial sarcoma biology, the cell-of-origin remains undefined. A mesenchymal stromal cell (MSC) specific CreERT2 line was employed to express SS18::SSX in fibroblasts and related cell types, resulting in 100% penetrant synovial sarcoma development in mice, with a median latency period of 16.2 ± 2.8 weeks. Murine tumours exhibited high concordance with human synovial sarcoma subtypes at the histological and molecular levels. Genetic refinement of the cell-of-origin revealed that synovial sarcomas derive from a rare Hic1⁺ Pdgfra⁺ Lgr5⁺ fibroblastic population. Furthermore, comparative transcriptomic analysis revealed the acquisition of a transformed phenotype initiated by the loss of a mature fibroblastic profile and subsequent unmasking of an epigenetically embedded embryonic MSC program. Adult and embryonic MSCs exhibited overlapping H2AK119ub and H3K4me3/H3K27me3 (bivalent) histone marks, while SS18::SSX-mediated transformation culminated in the widespread loss of H3K27me3 at these genes and their consequent transcription. Collectively, these studies define a rare MSC context, conducive for SS18::SSX-mediated transformation, and demonstrate that SyS tumorigenesis involves the induction and maintenance of an embryonic-like MSC phenotype.

Radiochromic films (RCFs) are ubiquitous in radiation oncology clinical and research settings to measure the radiation dose over a two-dimensional (2D) area due to their high spatial resolution, water-equivalency, and relative ease-of-use. Upon irradiation, the constituent monomers of the active layer of RCFs undergo polymerization, leading to a visible darkening that enables quantitative dosimetry. Quantitative RCF dosimetry requires film calibration against a reference dosimeter. Film darkening depends on various radiation-field and environmental parameters that need to be carefully considered to ensure the highest accuracy in film dosimetry. Several commercially available RCF models offer distinct dynamic dose ranges, allowing users to select appropriate options based on specific dosimetric needs. Here, we provide a review on the progress and practice of RCF dosimetry.

Durvalumab is a PD-L1 inhibitor that triggers a blockade resulting in enhanced anti-tumor responses related to increased T-cell activation. There is potential for numerous immune-related adverse events (irAEs) with this treatment, most of which have been shown to be effectively managed with high-dose steroids. Immunotherapy-related gastritis, while rare compared to other irAEs is an emerging concern as the use of immune checkpoint inhibitors (ICIs) increases.

This case study examines a 66-year-old female with extensive-stage small cell lung cancer (ES-SCLC) treated with durvalumab, alongside chemotherapy. Twenty-three months into treatment, she developed non-specific gastrointestinal (GI) symptoms including abdominal pain, appetite loss, and significant weight loss. Despite conservative management, resolution only occurred following the use of high-dose steroids, a finding consistent with immunotherapy-related gastritis. The patient then went onto a successful rechallenge of immunotherapy.

This case represents the first report on the rare occurrence of immune-related gastritis in an ES-SCLC patient who has been on immunotherapy for nearly 2 years. Current literature is limited in the understanding of underlying mechanisms of PD-L1-related irAEs and optimal management strategies for rare toxicities like gastritis in immunotherapy-treated cancer patients. This report aims to address the unmet need for further research on rare toxicities to immunotherapy in unique cases.

The incorporation of the current immunotherapy, GD2-targeting monoclonal antibodies, into the standard of care has moderately improved clinical outcomes in children with high-risk neuroblastoma (HR-NB); however, overall survival remains low. More than 50% of patients with HR-NB are refractory to or eventually develop resistance to anti-GD2 treatment. HR-NBs are generally known to have a low tumor mutational burden, are immunologically cold and possess an immunosuppressive tumor microenvironment. Understanding the mechanisms of immune evasion may provide novel targets for improving the efficacy of immunotherapies for these immunologically cold HR-NBs. Here, utilizing immunocompetent mouse models of immunologically cold HR-NB, we revealed a novel function of IGF2BP1 in promoting the immune escape of neuroblastoma tumors. We demonstrate that neuroblastoma cell-specific knockdown of IGF2BP1 favorably alters the tumor microenvironment of HR-NBs, turning these "immunologically cold" tumors into an immunogenic type, thereby priming them for anti-GD2 therapy-induced immune responses. Downregulation of IGF2BP1 in NB cells decreased the number of immunosuppressive T-regulatory and dysfunctional/exhausted CD8+ T cells and promoted the accumulation of effector MHCII +  macrophages at the tumor site. Importantly, knockdown of IGF2BP1 along with anti-GD2 immunotherapy induced a synergistic immunogenic effect and achieved a potent antitumor response in an HR-NB mouse model, with increased accumulation of effector CD8+ T cells and CD86+  macrophages but decreased MDSC numbers in the tumor microenvironment. Thus, disrupting NB cancer cell IGF2BP1-mediated immunosuppression is a potential approach for improving the efficacy of anti-GD2 immunotherapy towards HR-NBs.

Tumor consistency influences meningioma handling during surgery, but systematic biomechanical classifications are lacking. In this prospective study, 129 tumor slices from 20 meningiomas underwent amplitude-sweep oscillatory rheometry (1-100% strain, 1 Hz) to characterize storage modulus (G'), loss modulus (G″), damping (tan δ), yield strain, and strain stiffening. Curves were normalized, embedded by principal component analysis, and subjected to unsupervised clustering. Three reproducible viscoelastic phenotypes were identified (Cluster A: 29%, B: 61%, C: 9%) that differed significantly across baseline stiffness, stiffening slope, yield strain, and damping (all q < 1 × 10^-7). Cluster C, defined by high stiffness and elevated dissipation, was strongly associated with intraoperative hard grading (OR 82.8, 95% CI 11.0-623.2, p < 0.0001). Tumor-level stiffness index correlated with overall consistency (ρ = 0.48, p = 0.033), and the hard-phenotype fraction tracked both maximum (ρ = 0.54, p = 0.013) and minimum consistency (ρ = 0.53, p = 0.017). Entropy-based heterogeneity did not predict surgical consistency range. Clustering robustness was confirmed by bootstrap (ARI 0.81) and leave-one-tumor-out analysis (ARI 0.79). These findings suggest a quantitative biomechanical classification of meningiomas directly linked to operative handling.

Programmed cell death 4 (PDCD4) is a tumor suppressor characterized by its MA3 domain-mediated binding to eIF4A, which suppresses protein synthesis. Its primary functions include inhibiting cell proliferation, invasion, and metastasis, as well as promoting apoptosis. Leukemia is a clonally hematologic malignancy whose pathogenesis is driven primarily by the aberrant activation of key signaling pathways. These dysregulated signals promote enhanced self-renewal, uncontrolled proliferation, impaired differentiation, and blocked apoptosis, collectively arresting leukemic cells at various stages of development. Recent studies have demonstrated a close association between PDCD4 and leukemia development, indicating that PDCD4 regulates this process mainly by participating in abnormally activated signaling pathways. This review examines the expression and regulation of PDCD4 in leukemia, with a focus on its role as a molecular hub that connects the JAK/STAT, PI3K/AKT, and MAPK signaling pathways into a comprehensive network of leukemia pathways. Furthermore, the potential value of PDCD4 in the treatment of leukemia is discussed.

Programmed death-ligand 1 (PD-L1) partners with specificity Protein 1 (SP1) or signal transducer and activator of transcription 3 (STAT3) to modulate the transcription of growth arrest-specific 6 (GAS6) and early growth response protein 1 (EGR1), necessitating mediators to avoid feedback. Based on binding and stemness data, high mobility group A1 (HMGA1) and Small Mother Against Decapentaplegic3 (SMAD3) were identified as potential mediators in this context. While the SMAD3-P300-STAT3 complex facilitates SMAD3-STAT3 crosstalk, it remains unclear whether the PD-L1-HMGA1-SP1 or PD-L1-SMAD3-SP1 complexes bind to GAS6 and EGR1 promoters to regulate their transcription.

MG63 osteosarcoma cells and SW620 colon cancer cells with unidentified nuclear PD-L1 function were chosen for our study. Chromatin immunoprecipitation and co-immunoprecipitation assays were performed to evaluate SP1, HMGA1, SMAD3, STAT3, P300 and PD-L1 (also denoted CD274) enrichment at the GAS6 and EGR1 promoters; the existence of the PD-L1-(HMGA1 or SMAD3)-SP1 complexes; whether P300 binds to STAT3; and whether HMGA1 and SMAD3 bind to P300. The alterations in GAS6, EGR1 and PD-L1 mRNA levels after their combined over-expression and/or knockdown were assessed via qPCR. Two representative target genes identified via PD-L1 chromatin immunoprecipitation (ChIP)-seq were examined to determine whether HMGA1 and SMAD3 were enriched at their promoters.

PD-L1, HMGA1, SMAD3, SP1, P300 and STAT3 were enriched at GAS6 and EGR1 promoters in two cell lines. HMGA1 or SMAD3 antibody pulled down PD-L1 and SP1; PD-L1 antibody pulled down HMGA1, SMAD3 and SP1; P300 antibody pulled down STAT3; and, surprisingly, HMGA1 and SMAD3 antibodies pulled down P300. Combined over-expression or knockdown significantly altered GAS6, EGR1 and PD-L1 mRNA levels. PD-L1 ChIP-seq indicated 114 target genes, among which PD-L1 and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) were chosen to verify the promoter enrichment of HMGA1 and SMAD3.

Our study provides initial evidence that PD-L1 might form HMGA1- and SMAD3-dependent complexes to bind the GAS6, EGR1 and CD274 promoters, thus modulating the transcription of GAS6, EGR1 and PD-L1 mRNA in cancer and sarcoma cells.

Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) implicated in the onset and advancement of various human cancers. Among these, circFOXK2 has been linked to non-small cell lung cancer (NSCLC); however, its precise functions and underlying molecular mechanisms are not fully understood. This study shows the first experimental findings that circFOXK2 promotes NSCLC tumor progression by modulating the miR-328-5p/PKP3 signaling pathway. Levels of circFOXK2, miR-328-5p, and PKP3 were evaluated by qRT-PCR. Cellular (NSCLSC) proliferation was examined via CCK-8 assays, migratory capacity via wound healing, and invasive potential via Transwell assays. Potential binding interactions between miR-328-5p and circFOXK2 were first assessed using bioinformatic analysis and verified using a dual-luciferase reporter assay (DLRGAs). Regulatory relationships among circFOXK2, miR-328-5p, and PKP3 were further investigated through qRT-PCR analysis. Elevated expression of circFOXK2 and reduced levels of miR-328-5p were observed in NSCLC cell lines and tissues. Functionally, circFOXK2 enhanced cellular propagation, dissemination, and invasion in vitro. Mechanistic evaluation revealed that circFOXK2 upregulates PKP3 by acting as an miR-328-5p sponge. The findings demonstrate that circFOXK2 contributes to NSCLC tumorigenesis via modulation of the miR-328-5p/PKP3 pathway, identifying this signaling axis as a potential therapeutic target in NSCLC.

Obesity prevalence is rapidly increasing worldwide, necessitating diverse treatment approaches ranging from pharmacotherapy to surgical interventions. Tirzepatide, a recently approved dual GIP/GLP-1 receptor agonist, has shown therapeutic promise, but its impact on cancer-related pathways remains unclear. This in vitro study investigated the molecular effects of tirzepatide on colorectal cancer SW48 cells by assessing the expression of key regulatory genes, including NF-kB, p53, c-Myc, and CASP8, after treatment with varying tirzepatide concentrations compared to untreated controls. Results demonstrated significant upregulation of the tumor suppressor gene p53 and the pro-apoptotic gene CASP8 (notably a 68.37-fold increase in one treatment group, P = 0.0002), alongside increased c-Myc expression in higher dose groups. These findings suggest that tirzepatide exerts anti-cancer effects in colorectal cancer cells by suppressing NF-kB-mediated inflammation, activating p53-dependent tumor suppression, and promoting CASP8-mediated apoptosis. The concurrent upregulation of c-Myc with p53 and CASP8 highlights potential context-dependent regulatory mechanisms. Overall, this study provides mechanistic insights into tirzepatide's modulation of oncogenic signaling pathways, supporting its potential role in colon cancer therapeutics.

The gene encoding the RNA-binding motif protein 47 (RBM47) is highly expressed in epithelial cells and its down-regulation is characteristic for many types of cancer, among them colorectal cancer (CRC). However, the underlying mechanisms for this differential expression of RBM47 and its functional consequences during CRC progression have remained unknown. Here we found that RBM47 expression progressively decreases during CRC progression and is associated with poor prognosis and the metastatic CRC subtypes CMS4 and CRIS-B. In mice and humans RBM47 expression was highest in endoderm-derived tissues. The expression of forkhead box A1 (FOXA1), a transcription factor essential for the development of endoderm-derived epithelial tissues, showed a positive correlation with RBM47 expression in human tissues, as well as in primary CRCs and derived cell lines. Like RBM47, FOXA1 showed a down-regulation during CRC progression that is associated with poor prognosis and CMS4/CRIS-B. Ectopic FOXA1 induced RBM47 via directly binding to FOXA1 binding sites within the RBM47 promoter region. Up-regulation of RBM47 was necessary for FOXA1-mediated mesenchymal-to-epithelial transition (MET) and inhibition of CRC cell migration and invasion. RBM47 expression was silenced by CpG methylation in mesenchymal-like CRC cell lines. Moreover, epigenetic silencing of RBM47 in primary CRCs was associated with liver metastases. Therefore, the down-regulation of RBM47 is presumably initially mediated by loss of FOXA1 expression and subsequently fixed by CpG methylation of the RBM47 promoter. This down-regulation of RBM47 facilitates EMT and thereby promotes CRC metastasis. Finally, our results show that CpG hypermethylation of the RBM47 promoter represents a potential biomarker for metastatic CRC.