The distinct roles of GSK3 isoforms (GSK3α/β) in tumorigenesis and immune modulation remain poorly characterized across malignancies. We integrated multi-omics data from TCGA, GTEx, and single-cell RNA-seq to analyze GSK3α/β expression patterns in 31 cancers. Functional clustering, survival analysis (Cox regression), immune infiltration, and in vitro validation (AML cell lines treated with CHIR-99021) were performed. Integrated multi-omics analysis of 31 malignancies revealed divergent dysregulation of GSK3 isoforms: GSK3α was upregulated in 19 solid tumors but suppressed in AML, while GSK3β was elevated in 23 cancers and high-risk AML subtypes (FAB-M0/M1, P = 0.0013). GSK3β outperformed GSK3α as a pan-cancer diagnostic biomarker, achieving superior AUC in 9 tumors. Prognostically, high GSK3α predicted poor OS in ACC (HR = 8.80, P = 0.0047) and MESO (HR = 2.75, P < 0.0067), whereas GSK3β independently stratified cytogenetic-risk AML (HR = 4.22, P = 0.007). Immune profiling uncovered isoform-specific TME modulation: GSK3α correlated with protumorigenic immune infiltration (Treg/Th17, r = 0.38), contrasting GSK3β's broad negative associations with cytotoxic effectors (r = -0.27). Functional validation in AML THP-1 cells demonstrated that the GSK3 inhibitor CHIR-99021 (10 μM) significantly suppressed proliferation, induced apoptosis, and caused S-phase cell cycle arrest, concomitant with downregulation of c-Myc. These findings establish GSK3β as a key regulator of oncogenic programs in AML. This study provides a comprehensive pan-cancer atlas of GSK3 isoform-specific functionality, nominating GSK3β as a high-priority therapeutic target.

Many RNA viruses exhibit error-prone replication. Continuous generation of erroneous copies accelerates evolution. Avian leukosis virus subgroup J (ALV-J), an avian oncogenic virus, is a classical model virus for studying retroviruses. ALV-J's high mutation rates drive continuous evolution of its envelope and pathogenicity, posing significant challenges to the poultry industry. Here we employed deep mutational scanning to systematically assess envelope-wide mutation effects on ALV-J replication, integrating high-throughput sequencing with mutant libraries to identify critical envelope residues impacting viral fitness. Following 10 passages, the library virus exhibited enhanced replication capacity. Moreover, the library virus derived from SPF chickens displays screening results similar to those of the DF-1 cell-passaged virus. Most mutations were progressively eliminated during viral passaging, especially the first 80 amino acids of ALV-J envelope. Critical amino acid mutations, preferential deletion/insertion mutations and glycosylation patterns recapitulate evolutionary patterns observed in natural ALV-J isolates. Incorporation of all identified mutations into ALV-J J1 significantly increased in vivo replication efficiency and viral shedding of the recombinant virus. Functional study demonstrated that two key mutations independently promote viral replication: A64T enhancing entry via receptor-binding optimization, H304R promoting maturation through envelope cleavage efficiency. These insights enable targeted antiviral design by predicting evolutionary paths.

The actin-binding protein CAPG (Capping Actin Protein, Gelsolin Like) is implicated in oncogenesis, but its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study combined bioinformatic analysis of TCGA/GEO datasets, immunohistochemistry on clinical samples, and functional in vitro assays to define CAPG's significance in PDAC. We found CAPG significantly overexpressed in PDAC tissues (n = 179 tumor vs. 171 normal, p < 0.05), with levels correlating with advanced tumor stage (T3 vs. T1) and predicting poorer overall (p = 0.0085) and disease-free (p = 0.015) survival. In vitro, siRNA-mediated CAPG knockdown in PANC-1 and AsPC-1 cells markedly inhibited proliferation (CCK-8 assay) and migration (wound healing assay), and significantly sensitized cells to gemcitabine-induced apoptosis. Mechanistically, CAPG knockdown was associated with reduced ERK1/2 phosphorylation and Cyclin D1 expression, and ERK1/2 inhibition phenocopied the anti-proliferative and chemosensitizing effects. Our results establish CAPG as a negative prognostic biomarker in PDAC, demonstrate its critical role in driving proliferation and migration-potentially via modulating ERK pathway activity-and highlight its promise as a therapeutic target whose inhibition can enhance chemotherapy efficacy.

Genes encoding subunits of the mitochondrial tricarboxylic acid cycle enzyme complex succinate dehydrogenase (SDH) are a leading cause of the neuroendocrine tumour syndrome hereditary paraganglioma-pheochromocytoma. Pathogenic variants of SDHD and SDHAF2 confer a remarkable parent-of-origin tumour risk, in which paternally inherited variants cause tumours but maternally inherited variants do not. Formulated to explain this observation, the Hensen hypothesis proposes that loss of an (unknown) imprinted gene(s), together with the remaining wildtype SDH gene, is a prerequisite for tumour formation; in effect a three-hit hypothesis. This study had three objectives, first, as a test of the Hensen model, second, as a potential model for a disease for which no mouse or cell model currently exists, and finally, as a test of chromosome (Ch.) configuration to interrogate large genomic regions carrying an unknown phenotypic modifier. We crossed a gene knockout line (Sdhc, mouse Ch.1) to a Robertsonian chromosome line, Rb(1:7), harbouring the homologous gene imprinting centre (human Ch.11p15, mouse Ch.7) implicated in human tumourigenesis, to create a metacentric chromosome with characteristics of human chromosome 11. We developed 7 cohorts combining Sdhc (mouse Ch.1) wildtype or knockout with distinct configurations of Rb(1:7), confirming both paternal and maternal inheritance of Sdhc. We noted significant weight gain, and in heterozygote Sdhc KO-Rb/wt mice high levels of immune activation. Thyroid abnormalities, including lesions with papillary thyroid carcinoma-like features, were common (30-50%) in Sdhc knockout mice with both heterozygous and homozygous Rb chromosomes, regardless of mode of inheritance. We also observed a single case of bilateral pheochromocytoma in which loss of Sdhc was not the driver. While our findings did not recapitulate features of the Hensen Model, this study does suggest that chromosomal structure, even in the form of a seemingly innocuous single Robertsonian configuration, can dramatically impact clinical phenotype.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer, with limited treatment options due to the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) expression. This characteristic renders TNBC resistant to hormone-based and HER2-targeted therapies, leaving cytotoxic chemotherapy as the predominant strategy and highlighting the urgency for novel interventions. In this study, we investigated the mechanism of action of GL24, a potent 4-(phenylsulfonyl)morpholine-based small molecule with selective tumor suppression effects on metastatic TNBC cells, while being ineffective against TNBC cells derived from the primary tumor site, using gene co-expression analysis. By considering the distinct phenotypic responses induced by GL24, we tailored our co-expression analysis approach, selecting gene pairs that exhibited differential co-expression in effective cells while excluding gene pairs that also showed differential patterns in non-effective cells. Constructing a co-expression network from these differential pairs, followed by enrichment analysis and functional annotation, revealed specific gene interactions and molecular pathways associated with GL24-mediated TNBC inhibition. These insights supported the previously established findings that showed convergence on apoptosis based on differentially expressed genes, while also providing complementary information by highlighting pathways involved in metabolic alterations, proliferation, and migration or invasion. This expanded understanding advances the knowledge of the mechanisms of GL24 in combating TNBC.

Premenopausal women at familial or hereditary risk of ovarian cancer must weigh the risks and benefits of risk-reducing surgery. How they navigate this decision is not well understood.

The rapid development of therapies linked to molecular biomarkers has increased the importance of next-generation sequencing (NGS)-based tumor profiling to guide treatment decisions. Technology has enabled more comprehensive clinical testing; however, the optimal economic approach deserves investigation. This study evaluated the impact of testing using whole-exome, whole-transcriptome sequencing (WES/WTS) versus 50-gene panel tests from a US payer perspective.

Tumor-associated myeloid cells form a highly plastic and spatially organized immune compartment that plays a central role in tumor evolution, clinical outcome, and therapeutic response. Single-cell RNA sequencing has revealed extensive heterogeneity among macrophages, monocytes, neutrophils, dendritic cells, and related lineages, uncovering transcriptional programs linked to tumor promotion or immune activation. However, the dissociative nature of single-cell approaches disrupts tissue architecture, limiting insight into how myeloid cells interact with malignant, stromal, and lymphoid populations within intact tumors. Recent advances in spatial omics technologies address this limitation by preserving tissue context while enabling high-dimensional profiling of RNA and protein expression in situ. In this review, we synthesize emerging spatial proteomic and transcriptomic studies of tumor-associated myeloid cells, identify recurrent spatial architectures that govern tumorigenesis, prognosis, and treatment response, and examine analytical frameworks that translate spatial patterns into mechanistic understanding. By moving beyond descriptive spatial maps, we highlight unifying biological principles and translational opportunities that position myeloid spatial organization as a critical determinant of cancer progression and precision oncology.

Glioblastoma (GBM) is one of the most aggressive and treatment-refractory brain tumors. Temozolomide (TMZ) remains the standard chemotherapeutic agent but is frequently compromised by DNA-repair mechanisms, whereas tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis only in a subset of tumors due to strong intrinsic resistance. Here, we identify the Mu-2-related death-inducing gene (MUDENG/MuD) as the µ-subunit of adaptor protein complex 5 (AP5M1). TurboID-based proximity labeling revealed reproducible interactions with AP5B1 and AP5M1 subunits, as well as additional associations with AP1-3 complexes and nuclear proteins involved in cell-cycle regulation. These findings establish MuD as a multifunctional component of the AP5 complex that modulates cell-fate signaling in a context-dependent manner. Using MuD-mutant GBM cell lines, we demonstrate that MuD suppresses TRAIL-induced apoptosis by interfering with extrinsic and intrinsic pathways downstream of Bid, whereas it promotes TMZ-induced cytotoxicity through p53-dependent cell-cycle control and DNA-damage responses. Gene set enrichment analysis (GSEA) and functional profiling further revealed distinct MuD-associated interactomes linked to receptor endocytosis and genotoxic-stress pathways. Together, these results uncover opposing roles of MuD in TRAIL- and TMZ-mediated cell death, with MuD suppressing apoptotic signaling in response to TRAIL while modulating p53-dependent genotoxic stress responses that influence TMZ-induced cytotoxicity in glioblastoma.

Apoptosis and tumor suppression prevent cell proliferation in response to genomic damage. Polymorphisms in genes involved in these pathways can alter their function, facilitating the onset of cancer. Detecting these polymorphisms would assess the individual risk of developing different types of cancer. Therefore, the main goal of this study is to analyze the association between a set of genetic polymorphisms involved in apoptosis and tumor suppression and the risk of developing prostate cancer (PCa) in a population from Galicia. Accordingly, we performed a case-control study with 291 patients diagnosed with PCa and 249 healthy controls. A total of 19 genetic polymorphisms located in loci BCL2, CASP9, CASP8, CASP7, FAS, FASLG, BIRC5, TP53, MDM2, and MDM4 were genotyped. Their association with PCa was approached from a global perspective and stratified by the body mass index (BMI). Globally, a statistically significant association with PCa was found for polymorphisms rs1052576 (CASP9) and rs990431 (BIRC5), with carriers of the G allele (ORGA/AA = 2.14; p = 0.002) or the CC genotype (ORCC/CG = 1.92; p = 0.037), respectively, manifesting greater susceptibility to the disease. The analyses stratified by BMI yielded statistically significant results for polymorphisms rs1052576 (CASP9), rs3740286 (FAS), rs9904341 (BIRC5), rs2279744 (MDM2), rs937283 (MDM2), and rs1380576 (MDM4), with odds ratios between 2.47 and 8.00 in overweight or obese participants. These results indicate the differential effect of allelic variants of six SNPs on prostate cancer risk in patients with overweight or obesity. Further studies in larger cohorts should be conducted to confirm these findings.

Circular RNAs (circRNAs) are covalently closed, single-stranded RNAs generated via backsplicing. They are highly stable and evolutionarily conserved, making them promising candidates for cancer therapy and diagnosis. CircRNAs regulate cancer progression by modulating genome instability, angiogenesis, metastasis, stemness, and chemoresistance. They do so through mechanisms including microRNA (miRNA) sponging, protein interaction, translational templating, and transcription/translation regulation. CircRNAs play a critical role in cancer immunotherapy. They modulate immune checkpoint blockade (ICB) responses and cytokine secretion to reshape the tumor immune microenvironment (TME). CircRNAs also serve as stable platforms for neoantigen-based cancer vaccines and improve in vivo chimeric antigen receptor T cell (CAR-T) therapy by replacing unstable linear mRNA. Additionally, circRNAs are potential noninvasive biomarkers due to their abundance in body fluids and differential tumor-normal expression. Despite challenges such as unclear regulatory networks, off-target effects, and inefficient delivery, this review systematically summarizes the biogenesis of circRNAs, their functional mechanisms, their roles in cancer progression, and their applications in cancer immunotherapy. The review also highlights their utility as biomarkers and future translational directions, providing a focused overview of their potential to advance cancer immunotherapy.

The incidence of cancer increases markedly with aging, and the two processes share underlying molecular mechanisms. In the context of global population aging and rising cancer incidence, nine convergent hallmark axes have been identified: genomic instability, epigenetic drift, inflammation-immunity imbalance, microbiome dysbiosis, metabolic reprogramming, telomere attrition, stem cell exhaustion, cellular senescence, and autophagy dysfunction. These hallmarks constitute an integrated regulatory network that operates synergistically, antagonistically, or through bidirectional feedback across molecular, cellular, and microenvironmental levels. Genomic instability, epigenetic remodeling, chronic inflammation, microbiome dysbiosis, and metabolic reprogramming in aging often act synergistically to promote tumorigenesis, whereas telomere attrition and stem cell exhaustion primarily exert antagonistic, tumor-suppressive effects. Cellular senescence and autophagy dysfunction display context-dependent dual roles. Importantly, this network framework has direct relevance to cancer therapeutics. Although chemotherapy, radiotherapy, and immunotherapy effectively suppress tumor progression, they frequently induce therapy-induced senescence, characterized by cell-cycle arrest and a senescence-associated secretory phenotype, thereby accelerating functional decline and increasing long-term toxicities in older patients. The proposed "synergistic-antagonistic-dual" framework linking aging and cancer not only helps explain the disproportionate cancer burden in older adults but also supports a "one drug, two targets" therapeutic paradigm. Targeting these shared pathways has delayed aging phenotypes and suppressed tumorigenesis in preclinical studies and early clinical trials, highlighting the potential of integrated interventions that concurrently address aging and cancer.

Peto's paradox (Pp) results from the evidence that in mammals there is no obvious positive correlation between body size, lifespan, and cancer incidence. Posing the question of which mechanisms are responsible for this. Comparative studies searching for specific anticancer mechanisms as putative solutions to Pp have been undertaken in mammals. The result of these efforts are further inconsistencies leading to ad-hoc hypotheses and unnecessary complexity. In contrast to this, we present evidence that the cellular stress responses (CSRs), aimed at curtailing proteotoxic stress and assuring cell survival are necessary for enabling carcinogenesis. Yet, natural selection adjusts the performance of the CSRs according to the life history of each species and because of this, cancer is mostly delayed to the post-reproductive stage in all mammalian species, resulting in a limited impact of cancer on species fitness and viability. From this perspective, the need of evolving anticancer mechanisms, suggested by Pp is weakened or disappears and the paradox is likely resolved.

Emerging insights from immunometabolism underscore the importance of metabolic-immune interactions in shaping the brain tumor microenvironment and potentially influencing brain behavior and neurological outcomes. Although previous studies have suggested potential links between metabolites and risks of malignant brain tumor development, the causal relationship remains unclarified.

This study is aimed at distinguishing the phenotypes of low-grade gliomas based on the P53 signaling pathway gene set, revealing the transcriptomic changes in different phenotypes, screening phenotype-related feature genes, constructing a TP53 score, quantitatively describing TP53-related phenotypes, and predicting the response of glioma patients to chemotherapy.

N7-methylguanosine (m7G) is an important RNA modification involved in the regulation of gene expression during transcription. While its roles in mRNAs and tRNAs are increasingly understood, the distribution and function of m7G in long non-coding RNAs (lncRNAs), particularly in oral squamous cell carcinoma (OSCC), remain poorly understood. This study aimed to systematically characterize the m7G methylation landscape of lncRNAs in OSCC and investigate the oncogenic function and regulatory mechanism of the m7G-modified lncRNA DPY19L1P1.

Acute myeloid leukemia (AML) is an aggressive and molecularly diverse hematologic malignancy with unfavorable clinical outcomes and limited options for targeted therapy. This study investigated whether polypyrimidine tract-binding protein 1 (PTBP1), an RNA-binding protein (RBP), affects AML progression by binding to WNK lysine-deficient protein kinase 1 (WNK1).

Centromere protein A (CENPA) is a histone H3 variant essential for centromere function and has been implicated in tumorigenesis in several cancers. However, its clinical significance and biological role in endometrial cancer (EC) remain poorly characterized. This study aimed to elucidate the oncogenic function and underlying mechanisms of CENPA in EC progression.

Collagen type XI alpha 1 (COL11A1) is overexpressed in pancreatic cancer and is often associated with poor survival, chemoresistance, and tumor recurrence. However, the role of COL11A1 in pancreatic cancer remains poorly understood.

Gastric cancer (GC) is among the most frequently diagnosed malignancies worldwide. Identifying novel therapeutic targets is of great significance.