The prognosis of gastric cancer with peritoneal dissemination is poor because of its resistance to chemotherapy. To investigate the mechanism of drug resistance in peritoneal metastasis, cancer organoids were established from the ascites of a patient with peritoneal metastases of gastric cancer. The histological characteristics of the tumors were preserved in the organoids. A co-culture system was established by overlaying human-derived mesothelial cells on gastric cancer organoids embedded in type IA collagen, mimicking peritoneal dissemination foci. When co-cultured with mesothelial cells, the proliferation of ascites-derived gastric cancer organoids and other primary gastric cancer organoids was suppressed. Soluble factors derived from mesothelial cells were involved in suppressing cell proliferation. Organoids in co-culture showed reduced sensitivity to paclitaxel. This co-culture model may provide a useful platform for studying drug resistance mechanisms in the microenvironment of gastric cancer peritoneal metastases.

The global incidence of thyroid carcinoma (THCA) is increasing. Although generally indolent with a favorable prognosis, a subset of cases exhibits aggressive progression. Conventional chemotherapy frequently induces severe systemic toxicity owing to poor target specificity, highlighting the need for more targeted therapeutic approaches. The HGF/c-MET signaling pathway plays a pivotal role in tumorigenesis and disease progression, promoting malignant tumor development through diverse mechanisms, including cell proliferation and migration. By combining integrated multi-omics bioinformatics analysis with functional experiments, this study demonstrates that the MET gene represents a promising theragnostic marker for THCA. Specifically, our study demonstrated: (1) The MET gene is significantly overexpressed in THCA tissues compared to normal controls; (2) This dysregulation is closely associated with aggressive malignant phenotypes, including enhanced tumor progression, increased metastatic potential, reduced survival, and immune-suppressive characteristics; (3) Retrospective clinical case analysis indicated that the lymph node metastasis rate was significantly elevated in the MET high-expression group relative to the low-expression group; (4) RNA interference (RNAi)-mediated MET knockdown resulted in a marked decrease in the migratory and invasive capacities of thyroid cancer cells in vitro. Collectively, these findings not only identify MET as a robust molecular classifier for THCA but, more critically, uncover its therapeutic potential as an actionable target within the HGF/c-MET axis for refractory THCA, providing both experimental evidence and a theoretical framework for developing precision diagnostic and therapeutic strategies.

Breast cancer (BC) is a major contributor to cancer-related mortality, emphasizing the need to identify molecular biomarkers for effective disease management, accurate prognosis prediction, and preventive interventions. The objective of this research was to examine the association between tumor protein p53 (Tp53) expression and the stage of the disease. The study involved the participation of 70 individuals diagnosed with BC. RNA samples were extracted, and the expression levels of Tp53were evaluated using real-time RT-PCR. The collected data were subsequently analyzed utilizing SPSS software. The findings revealed an up-regulation of p53 expression in the subjects with BC. The study found that the expression of the Tp53 gene varies across different stages of BC. Stage 4 showed the highest expression, while stage 1 had no detectable expression. Grades 2 and 3 had higher expression levels, suggesting a correlation between tumor aggressiveness and increased Tp53 gene expression (P < 0.001). Patients aged 40 or above had higher expression levels compared to those below 40 (P < 0.001). Individuals who had a familial history of BC displayed notably elevated levels of Tp53 gene expression (P < 0.001). These findings demonstrate the dynamic nature of Tp53 gene expression in relation to disease stage, patient age, familial history, disease duration, grade, and childbirth number. This indicates the potential of the Tp53 gene as a biomarker for early-stage BC, as its minimal expression or absence may indicate early-stage disease.

Tumor cell plasticity in novel microenvironments is central to the integration and subsequent growth of metastatic cells. However, the functional consequences of tumor cell integration with central neurons remains understudied. Here, we address this question using small cell lung cancer (SCLC), which has an extraordinary propensity to metastasize to the brain in humans. Transcriptomic and electrophysiological analysis of SCLC cells in neuronal microenvironments reveal a heterogeneous population of synapse-forming SCLC cells with neurons. While a proportion of neuron-SCLC synapses are blocked by AMPA receptor antagonists, we also find a sensitivity of these synapses to GABAA receptor inhibition. The functional integration of SCLC with central neurons induced multiplicative synaptic upscaling between neurons and dysregulated neuronal excitability. Aberrant excitation in human neurons with SCLC was sustained by synaptic NMDA receptor activation and can be reduced by the FDA approved NMDA receptor blocker memantine. These findings reveal strategies to normalize tumor-induced exacerbation of aberrant neuronal activity.

Cannabinoids have emerged as promising agents in cancer research due to their antitumor properties. While their effects on tumor growth and survival are well documented, their influence on immune checkpoint regulation remains poorly understood. Here, we investigated the effects of cannabidiol (CBD) and a high-CBD extract (CBD-HCE) on HLA-G expression in human choriocarcinoma JEG-3 cells, a non-classical HLA class I molecule linked to tumor immune escape. Safe concentrations of CBD and CBD-HCE were determined by MTT assays. Apoptosis (Caspase-3), proliferation (Ki-67), and migration (wound healing and MMP-9 immunostaining) were assessed, and HLA-G expression was quantified by RT-qPCR and immunocytochemistry. Both CBD and CBD-HCE reduced cell proliferation and migration, increased apoptosis, and significantly downregulated HLA-G expression at both the mRNA and protein levels. This inhibitory effect was dose- and time-dependent, and fully reversible after treatment withdrawal, indicating a dynamic and CBD-dependent modulation. These results provide the first experimental evidence of HLA-G downregulation by CBD and CBD-HCE, highlighting a novel immunomodulatory mechanism with potential therapeutic implications. By simultaneously impairing tumor viability and reversing immune evasion, CBD-based compounds may enhance antitumor immunity and potentiate immunotherapy efficacy. Further research involving additional tumor cell lines, in vivo models, and immune-relevant systems are necessary to validate and expand upon these findings.

Acute Myeloid Leukemia (AML) is a genetically and clinically heterogeneous disease that can develop at any age. While AML incidence increases with age and distinct genetic alterations are observed in younger versus older patients, current classification systems do not incorporate age as a defining factor. In this study, we analyzed RNA-seq data from 404 AML patients at initial diagnosis, leveraging a k-mer-based machine learning approach to uncover age-related transcriptomic differences in favorable and adverse risk groups. Our model achieved over 90% accuracy in risk prediction and identified key gene signatures distinguishing ELN2017 favorable and adverse groups. From these signatures, we selected prognostic biomarkers with significant impacts on survival. Additionally, we explored the biological context underlying transcriptomic complexity across age groups, revealing distinct tumor profiles and differences in immune and stromal cell populations, particularly in older patients. These findings underscore the importance of age-related molecular features in AML and provide new insights for risk stratification and therapeutic targeting.

SF3B6 functions as a splicing factor, and is closely associated with the malignant progression of multiple cancer types, including breast cancer. However, its underlying mechanism is largely unknown in breast tumor cells. In this study, we investigated the molecular mechanism and downstream targets of SF3B6 by transfecting the siRNA of SF3B6 (siSF3B6) into MDA-MB-231 cells and combining with high-throughput transcriptome sequencing (RNA-seq) and improved RNA immunoprecipitation sequencing (iRIP-seq) technology. We found siSF3B6 significantly repressed cellular proliferation and migration levels, but increased apoptosis levels of MDA-MB-231 cells. Downstream RNA-seq analysis revealed that SF3B6 silencing resulted in widespread changes in differentially expressed genes (DEGs) and regulatory alternative splicing events (RASEs) that were involved in inflammatory response and immune regulatory pathways, such as the NF-κB signaling pathway. The iRIP-seq analysis indicated that SF3B6 can regulate the gene expression and alternative splicing profile by directly interacting with its targeting mRNAs. Further analysis showed that SF3B6 potentially contributes to the malignant properties of TNBC by regulating the expression and splicing of key oncogenes, including PPM1F and FASN, and tumor suppressor genes, including RLF and RECQL4, which were validated by RT-qPCR experiment. In summary, this study highlights the crucial molecular role of SF3B6 in breast cancer cells, providing new insights into its potential as a biomarker or valuable target in breast cancer diagnosis and treatment in future.

Tumor necrosis factor (TNF)-induced RIPK1-mediated cell death is implicated in various human diseases. However, the mechanisms RIPK1-mediated cell death is regulated by metabolic processes remain unclear. Here, we identify hexokinase 2 (HK2), a critical regulator of glycolysis, as a suppressor of TNF-induced RIPK1 kinase-dependent cell death through its non-metabolic function. HK2 inhibits RIPK1 kinase activity through constitutively phosphorylation at serine 32 of RIPK1. Inhibition of RIPK1 S32-phosphorylation results in RIPK1 kinase activation and subsequent cell death in response to TNFα stimulation. We further show that HK2 is elevated under pathological conditions including liver ischemia-reperfusion (IR) injury and hepatocellular carcinoma (HCC) via the transcriptional factor HMGA1. Moreover, the upregulation of HK2 in the liver confers protection against liver IR injury mediated by RIPK1 kinase, while depleting HK2 in HCC cells enhances TNFα-induced cell death and synergistically improves the efficacy of anti-PD1 therapy in an HCC model. Thus, the findings reveal a potential therapeutic avenue for RIPK1-related diseases through manipulating HK2 non-metabolic function.

Perineural invasion (PNI) is implicated in tumor invasion, metastasis, cancer-related pain, and adverse clinical outcomes across various malignancies. Nonetheless, the core genes and molecular mechanisms underlying PNI in colorectal cancer (CRC) remain inadequately understood. The objective of our study was to identify key genes associated with PNI in CRC through bioinformatic analysis. Transcriptomic and clinical data for CRC were obtained from the Cancer Genome Atlas (TCGA) dataset. Using the limma package, we identified 2,446 differentially expressed genes (DEGs) between CRC samples with and without PNI. Additionally, 1,793 immune-related genes (IRGs) were obtained from the ImmPort database. The intersection of differentially expressed immune-related genes (DEIRGs) was subsequently employed for functional enrichment analysis and the development of risk models. A novel prognostic model related to PNI was successfully developed and validated, demonstrating its independent prognostic value in CRC. Cardiotrophin-like cytokine factor 1 (CLCF1) was identified as a key prognostic marker associated with PNI in CRC, with elevated expression observed in tumor samples. CLCF1 was shown to enhance the proliferation, invasion, and migration capabilities of CRC cells, suggesting its potential as a therapeutic target for CRC.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet predicting patient response remains a major challenge. Carcinoma ecotypes, which capture the cancer-immune interactions, show promise as prognostic biomarkers but remain untested in real-world settings. We compile and analyze the ORIEN Avatar ICI cohort of 1610 patients with matched gene expression data from a broader dataset of 14,997 individuals. Using EcoTyper-based immunophenotyping, we define ecotypes and assess their prognostic value across cancers, with a focused analysis in melanoma. Distinct cell states and ecotypes are consistently associated with survival outcomes across cancer types. We further develop a melanoma-specific ICI predictive model and validate it using data from the phase III ECOG-ACRIN E1609 trial as well as in external harmonized melanoma datasets. Together, these findings establish an ecotype-based framework and provide real-world evidence for their translational utility as clinically actionable biomarkers with prognostic and predictive value to guide ICI therapy.

Pancreatic cancer (PDAC) is one of the most lethal malignancies. The current mainstay therapy for metastatic disease is cytotoxic chemotherapy. The increasing application of molecular profiling and precision oncology plays a significant role in the emergence of investigational targeted therapies. To date, there are a small number of targeted therapies that are FDA-approved and/or endorsed by guidelines. Major emerging targets in PDAC are KRAS, claudin, MTAP, and others. This review provides a brief overview of FDA-approved or guideline-endorsed targeted therapies and summarizes major emerging therapies in the field that are deemed to have high potential to improve outcomes in PDAC.

IntroductionThe expression of Human Epidermal Growth Factor Receptor-2 (HER2/neu) has shown significant therapeutic implications in malignancies, particularly in breast and gastric cancer. Therefore, the interest in studying HER2 in other malignancies, including colorectal cancer (CRC), has increased. However, the prevalence of HER2 overexpression in CRC remains debatable, with conflicting data. To address this uncertainty, this study aimed to investigate HER2 expression in CRC in Jordanian patients and to assess its association with clinicopathological characteristics, as well as the survival outcome.MethodsSixty-nine formalin-fixed, paraffin-embedded tissue blocks of CRC cases were included along with their corresponding patient's clinicopathological data. Tissue-microarray (TMA) were constructed and stained using anti-HER2/neu monoclonal antibody. HER2 scoring was performed using the HERACLES criteria. Fisher's exact test/Chi-squared test were used to investigate the association between HER2 scores and the clinicopathological data. Survival analysis was evaluated using Kaplan-Meier curves.ResultsHER2/neu positivity of any degree was expressed in 30 cases (43.5%). Twenty-five cases (36.2%) were scored 1 + and 4 (5.8%) scored 2+. Only one case (1.5%) was scored as 3+, representing the single positive case. In comparison, 39 cases (56.5%) showed no HER2/neu protein expression and were scored as (0). Two of the four cases that were scored (2+) required FISH testing to confirm the positivity for HER2 overexpression, which was not available. No significant associations were found between HER2/neu expression and clinicopathological parameters or survival rates. However, cases with either 2+ or 3+ HER2/neu scores were associated with worse overall survival (OS) and event-free survival compared to cases with a score of 1+ or no expression (score 0).ConclusionsThe prevalence of HER2/neu overexpression in CRC among Jordanian patients is low, with only 1.5% of the study sample exhibiting HER2/neu overexpression. A trend towards poor outcome was observed in patients with HER2/neu overexpression.

BackgroundHepatocellular carcinoma (HCC) is a major global health burden, with limited tools for early diagnosis and prognosis. This study explores serum-derived exosomal miR-1275 as a potential non-invasive biomarker for HCC.MethodsExosomes were isolated from serum samples of 50 HCC patients and 50 matched healthy controls. miR-1275 expression was quantified by qRT-PCR and compared with traditional biomarkers (AFP, CEA, CA199, DCP, AFP-L3%). Diagnostic performance was evaluated using ROC curves. Bioinformatic analyses, including TCGA pan-cancer data, target gene prediction, and pathway enrichment, were performed to explore regulatory mechanisms.ResultsExosomal miR-1275 levels were significantly reduced in HCC patients and correlated with advanced clinical stage, tumor burden, and metastasis. miR-1275 showed strong diagnostic value (AUC = 0.869), outperforming CEA and CA199, and improved significantly when combined with other biomarkers (AUC = 0.982). UBE2V1 was identified as a key miR-1275 target involved in cancer-related pathways, including ubiquitination and mTOR signaling.ConclusionSerum exosomal miR-1275 is a promising biomarker for early diagnosis and prognosis of HCC. Its integration into multimarker panels could enhance clinical decision-making and patient management.

Cancer genes break free from the regulatory constraints of chromosomes.

Epigenetic and transcriptional dysregulation plays a fundamental role in tumor lineage plasticity (LP). However, the underlying mechanisms, especially for the initial events of LP development, are still poorly understood. Here, we report that in progression of prostate cancer from adenocarcinoma to treatment-induced neuroendocrine prostate cancer (t-NEPC), anti-androgen receptor (AR) signaling inhibitors (ARSIs) reprogram the function of circadian regulator/nuclear receptor REV-ERBα by switching its target gene programs from kinase signaling and metabolic programs to programs of LP, which includes neurogenesis, stem cell, and epithelial-mesenchymal transition as well as over fifteen LP drivers including POU3F2/BRN2, ASCL1, FOXA2, ONECUT2, and MYCN. Unexpectedly, REV-ERBα facilitates the chromatin occupancy of BRN2, ASCL1, and FOXA1 in their activation of LP programs, thus functioning as a master regulator of ARSI-induced LP driver network. Mechanistically, REV-ERBα induces chromatin accessibility and H3K27ac modification at promoters of LP genes through its recruitment of BRD4 and p300. Overexpression of REV-ERBα alone is sufficient to induce LP and neuroendocrine phenotype and confers resistance to ARSI in adenocarcinoma cells. Loss of REV-ERBα potently inhibits NEPC cell growth and abolishes the expression of LP drivers and gene programs. Pharmacological inhibition of REV-ERBα exhibits high potency in blocking the growth of NEPC tumors including patient-derived xenografts. Our findings reveal that therapy-induced LP development entails a coordinated induction of a network of LP drivers and that REV-ERBα is an unexpected master regulator of the network and a promising therapeutic target for treatment of advanced prostate cancer such as NEPC.

The information-theoretic approach can shed light on the role of groups of correlated elements within a network. While there are already established methods for measuring new information, storage and transmission, the definition and application of methods for measuring information change remains an unresolved challenge. The change of information in a network is associated with redundancy and synergy between systems that share information about a target. Redundancy involves shared information about the target that can be retrieved using the individual source systems, while synergy involves information that can only be obtained by sharing the systems. A more refined approach, called partial information decomposition (PID), separates the unique, redundant and synergetic contributions of the shared information. However, these contributions cannot be directly derived from the classical measures of information theory. In this work, we apply PID approach to publicly available microarray gene expression data from 2 different experiments derived from patients affected by HCC and ASD. By comparing sample and gene synergy clusters with classical correlation clusters, we uncover higher order behaviours, such as differential genes and enriched functions closely linked to diseases phenotype, that emerge with this novel approach. These findings and further applications of this approach to gene expression data could shed light on the genetic aspects related to physiological aspects of complex diseases.

Vestibular schwannoma (VS) is a benign tumor originating from Schwann cells, and its molecular pathogenesis remains poorly understood. Increasing evidence suggests oxidative stress (OS) plays a critical role in tumor development, but its involvement in VS is largely unexplored.

Osteosarcoma is the most common malignant bone tumor in children and adolescents, characterized by high heterogeneity and a complex tumor microenvironment (TME). Despite multimodal treatments, survival rates have stagnated, highlighting the need for new therapeutic options. Single-cell RNA sequencing (scRNA-seq) offers a powerful tool to dissect heterogeneity and uncover mechanisms of progression and immune evasion. A narrative literature review, guided by PRISMA principles, was conducted through October 2024 via PubMed and Scopus databases to assess scRNA-seq contributions to osteosarcomagenesis. A total of 107 studies were analyzed to highlight the identification of tumor subpopulations, signaling pathways, diagnostic and prognostic biomarkers, and therapeutic assessments. Our analysis highlights the critical role of scRNA-seq in revealing the complexity of the osteosarcoma TME. Studies identified distinct immune and non-immune cell subpopulations, with TXNIP+ and IFIT1+ macrophages, KAZALD1, EGFL7, TNFSF11, and TRAIL receptors emerging as potential therapeutic targets. scRNA-seq has elucidated mechanisms of tumor progression and metastasis, including CD24 expression, and enabled the discovery of immune and stromal biomarkers within the TME. It also revealed novel therapeutic strategies, such as targeting Tregs via CXCR4 inhibition, CAFs through LOX and SERPINE1 modulation, and MCL1 in metastatic niches. Additionally, it uncovered promising drug candidates-etoposide, mevastatin, oxfendazole, HDAC inhibitors, and TIGIT blockade-as well as immunotherapies like PD-1 inhibition and adoptive CD8+ T cell therapy. scRNA-seq has transformed insights into osteosarcoma by exposing key cellular dynamics and potential therapeutic targets. While technical challenges remain, it paves the way for more personalized and effective treatment strategies. However, the current findings are subject to limitations, including technical biases in single-cell protocols and the exclusion of non-English literature, which may affect generalizability.

Although low-grade glioma (LGG) patients usually enjoy an active familial and socio-professional life, their ability to practice sports was poorly studied. Here, the capability to resume high-level sports following awake surgery (AS) in LGG patients who performed intensive sport activities before resection was investigated.

Non-small-cell lung cancer (NSCLC) is associated with high mortality. Beclin 1 (BECN1), an autophagy regulator, and ferroptosis, a lipid peroxidation-driven cell death, are both linked to cancer suppression. This study examines whether the BECN1 activator peptide, Tat-Beclin 1, induces ferroptosis in NSCLC by targeting solute carrier family 7 member 11 (SLC7A11). BECN1 expression in NSCLC tissues and cells was assessed using RT-qPCR, western blot, and immunohistochemistry. Functional assays included CCK-8 for cell viability, C11-BODIPY for lipid peroxidation, glutathione (GSH) and glutamate release, glutathione peroxidase 4 (GPX4) activity, and western blotting for iron metabolism markers (ferritin heavy chain 1 [FTH1], ferritin light chain [FTL], and transferrin receptor [TFRC]). BECN1-SLC7A11 interactions were examined using co-immunoprecipitation and immunofluorescence. BECN1 was knocked down using small hairpin RNA (shRNA), and its effects on ferroptosis were evaluated. System Xc⁻ activity was assessed in control, Tat-beclin 1, Tat-beclin 1 + shRNA-NC, and Tat-Beclin 1 + shRNA-BECN1 groups. Tumor suppression by Tat-beclin 1, erastin, and their combination was assessed in vivo using xenograft models. BECN1 expression was downregulated in NSCLC tissues and cells. Treating NSCLC cells with Tat-beclin 1 upregulated BECN1 expression and promoted ferroptosis, as evidenced by increased lipid peroxidation and malondialdehyde content, reduced GSH and GPX4 activity, and decreased cell viability, without affecting Fe2+ levels or the expression of iron metabolism-related proteins (FTH1, FTL, and TFRC). Knocking down BECN1 attenuated these effects, confirming its central role. BECN1 interacted with SLC7A11 to inhibit system Xc⁻, an effect abolished by knocking down BECN1. Co-treatment with Tat-beclin 1 and erastin enhanced BECN1-SLC7A11 complex formation, more strongly inhibited system Xc⁻, enhanced lipid peroxidation, inhibited the Nrf2-Keap1 signaling pathway and significantly suppressed tumor growth in vivo. Tat-beclin 1 promotes ferroptosis and tumor suppression in NSCLC by activating BECN1 and inhibiting SLC7A11-mediated system Xc⁻ activity.