Breast malignant phyllodes tumours are rare fibroepithelial neoplasms arising from periductal stromal cells, characterized by rapid progression and a high recurrence rate. The poor prognosis largely stems from the lack of effective therapeutic strategies, underscoring the insufficient understanding of their molecular mechanisms and therapeutic targets. Moreover, most previous studies have mainly focused on the tumour core, while the molecular features of the surrounding peritumoural tissue remain insufficiently explored.

Fusion protein AML1-ETO and chemokine receptor CXCR4 are crucial therapeutic targets for AML, the former plays a key role in differentiation blockade and leukemogenesis, and the latter is closely associated with drug resistance and relapse. This work developed a unified platform (referred as to E5-LNP@siAE) to integrate AML1-ETO-targeted RNA interference (RNAi) and CXCR4 antagonism by employing lipid nanoparticle (LNP) technology and antagonistic peptide E5 modification. The E5-LNP@siNC was slightly negative charged with 121.8 nm in diameter, showing homogenous spherical morphology and stability in PBS and 10% FBS. The E5-LNP@siAE could be specifically taken up by Kasumi-1 cells, down regulated levels of AML1-ETO, p-Erk and p-p38, and E5-LNP@siNC inhibited the CXCL12-mediated migration. In a refractory AML mouse model, E5-LNP@siAE monotherapy significantly reduced AML cells in peripheral blood, as well as infiltrations in the liver, lung and spleen. The expressions of CD11b, CD41a and Ter119 were upregulated while c-Kit decreased in the spleen of AML mice received E5-LNP@siAE treatment. The differentiation inductive effects were also observed in bone marrow mononuclear cells separated from AML patients with t(8;21) translocation. Moreover, E5-LNP@siAE significantly enhanced the therapeutic efficacy of doxorubicin (DOX) in the AML mice, evidenced by the reduced AML cells in peripheral blood, bone marrow and multiple organs, meanwhile, did not bring negative impacts on the counts of red blood cells and platelets. Consequently, the combination regimen achieved the much better result of survival prolongation than E5-LNP@siAE monotherapy, and the other control groups did not show therapeutic effects on the survival of the AML mice.

Distal cholangiocarcinoma (dCCA) is a malignant tumor characterized by a challenging diagnosis, high invasiveness, and extremely poor prognosis. Research on dCCA is limited by the scarcity of reliable patient-derived preclinical tumor models. This study established a novel human distal cholangiocarcinoma cell line, CBC3T-3, and systematically characterized its biological properties, genomic features, and potential for clinical application. This cell line was extracted from postoperative distal cholangiocarcinoma tumor from a 54-year-old male patient. It was stably passaged (> 50 generations) through primary culture and condition optimization, preserving the same pathology as that of the primary tumor. Whole-exome sequencing (WES) confirmed somatic mutations, tumor mutation burden, single-sample clonal structure, driver genes, and drug resistance genes in CBC3T-3 cells, revealing their genomic characteristics. Functional assays demonstrated that CBC3T-3 cells exhibit strong capabilities for proliferation, migration, and invasion in vitro. In a subcutaneous xenograft model in immunodeficient mice, palpable tumor nodules developed within 4 weeks, reflecting the clinical characteristics of rapidly progressive disease. Drug sensitivity analysis revealed that, compared with TFK-1 cells, CBC3T-3 cells presented significantly greater responses to paclitaxel, gemcitabine, and oxaliplatin but relatively poor responses to 5-FU and cisplatin. The integration of drug resistance gene findings from WES suggests that TP53 missense mutations may mediate primary resistance to cisplatin. The establishment of the CBC3T-3 cell line enhances the research toolkit for dCCA. Its genomic characteristics and functional plasticity provide a reliable preclinical tumor model for developing precision therapies and investigating drug resistance mechanisms.

A disintegrin and metalloprotease with thrombospondin type 1 repeats, 1 (ADAMTS1) is a metalloproteinase essential for ovarian follicle development and ovulation. It is also involved in organizing vascular and lymphatic networks within ovary. ADAMTS1 is expressed by granulosa cells in ovarian follicles, and its expression and function are regulated by gonadotropins, follicle-stimulating hormone, and luteinizing hormone. This enzyme cleaves extracellular matrix (ECM) proteins to remodel the ECM and provide the necessary space for the growing ovarian follicles. ADAMTS1 is also essential for breaking down the follicular wall by cleaving proteoglycans, thereby releasing oocytes during ovulation. Loss of ADAMTS1 impairs remodeling of the ECM and decreases ovulation in mice. Dysregulation of ADAMTS1 is also linked to pathological conditions like polycystic ovary syndrome and premature ovarian failure, highlighting the precise activity of this enzyme. This chapter discusses the known and potential functions of ADAMTS1 in ovarian biology.

Isocitrate dehydrogenase 1 (IDH1) mutations confer distinct biological properties to gliomas, including the reshaping of the tumor immune microenvironment. While T cell dysfunction in glioblastoma has been extensively characterized, the role of innate lymphoid cells (ILCs)-critical regulators of tissue homeostasis and early immune responses- remains poorly understood.

Resistance to 5-fluorouracil (5-FU) remains a major challenge in the treatment of colorectal cancer (CRC). Here, we identify ETS variant transcription factor 7 (ETV7) as significantly upregulated in CRC tissues and cell lines, with elevated expression associated with poor clinical prognosis. Functional assays demonstrate that ETV7 enhances CRC cell proliferation, invasion, and resistance to 5-FU. Mechanistically, ETV7 transcriptionally upregulates CXCL1, leading to increased neutrophil recruitment and enhanced formation of neutrophil extracellular traps (NETs). The resulting NETs-enriched tumor microenvironment promotes tumor aggressiveness and chemoresistance. Pharmacological inhibition of CXCL1 or degradation of NETs effectively attenuates ETV7-driven malignant phenotypes in vitro and in vivo. Collectively, these findings establish an ETV7-CXCL1-NETs axis that contributes to 5-FU resistance in CRC and suggest that targeting this pathway may improve chemotherapy response.

Tumor mutational burden (TMB) and PD-L1 are established biomarkers for guiding immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC). As ICI use expands into early-stage disease, we explored the feasibility of using TMB, which can be determined via a comprehensive genomic profiling assay along with EGFR and ALK genomic alterations, as a biomarker for outcomes in both neoadjuvant and adjuvant settings. TMB-high status (≥10 mut/Mb) showed a numerically higher, but not statistically significant, rate of pathological complete response among patients receiving neoadjuvant ICI and significantly associated with more favorable time to recurrence in patients receiving adjuvant ICI, particularly among patients with PD-L1 expression <50%. TMB should be considered in future early-stage NSCLC ICI clinical trials to further validate these results.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The higher incidence and earlier onset of HCC in sub-Saharan Africa suggest a potential role for a genetic predisposition. This study evaluated the association of TERT-rs2242652-(A), a variant linked to lower HCC risk, with HCC in populations from Ghana, Nigeria, and Cameroon, compared with a population from the United States.

Gliomas exhibit significant prognostic heterogeneity, and single-omics data/existing technologies struggle to balance multi-omics integration efficiency, prediction accuracy, and clinical adaptability-hindering the clinical translation of precise prognostic assessment. Focussing on glioblastoma (GBM) and lower-grade glioma (LGG), this study proposes an integrated solution: three-step multi-omics feature selection combined with the limited random forest (FRF) model, using TCGA-derived transcriptomic, genomic, epigenomic and clinical survival data. Prognosis-related features are first screened using univariate Cox regression, refined by random forest-based feature importance for dimensionality reduction and then integrated into a multi-omics matrix through sample matching. The FRF model balances efficiency and accuracy by limiting decision tree number and depth, optimising node splitting criteria, and adding a dual-weighted correction mechanism. Results show that FRF achieves an AUC of 0.96 for GBM, outperforms logistic regression (LR) and support vector machine (SVM) across all LGG metrics, and reduces training time to minutes-meeting the 2-h clinical prognostic demand. Ablation experiments confirm that the multi-omics model improves performance by 11.63% compared with the optimal single-omics model, with core features consistent with glioma molecular mechanisms. This resolves the challenge of rapid integration and precise prediction, providing an efficient tool for glioma prognostic assessment and supporting multi-omics clinical translation.

Deciphering the mechanisms underlying antitumor immunity is critical for improving cancer immunotherapy efficacy. Here, we identify WFDC21P (lnc-DC) as a positive regulator of antitumor immunity through promoting the activation of the RNA-sensing retinoic acid-inducible gene-I (RIG-I) pathway in triple-negative breast cancer (TNBC). WFDC21P directly binds to RIG-I-interacting protein G3BP1 and is required for a rapid assembly of functional G3BP1-RIG-I-double-stranded RNAs condensates via phase separation, which enables robust activation of RIG-I. WFDC21P is downregulated in TNBC tissues and correlates with less CD8+ T cell infiltration in tumors and worse outcome of patients. WFDC21P knockdown in TNBC cells markedly dampens RIG-I activation and reduces the expression of IFN-stimulated genes, including MHC-I and PD-L1. In syngeneic tumor models, WFDC21P expression not only suppresses tumor growth by augmenting the infiltration and cytotoxic function of CD8+ T cells but also improves the response to immune checkpoint blockade, thus providing a compelling combination immunotherapy strategy for treating triple-negative breast cancer.

This study presents a nationwide infrastructure for the collection and utilization of gynecologic cancer biospecimens, established through the Korea Biobank Project. We comprehensively describe the biobanking strategy, quality control protocols, and development of secondary resources to support future translational and discovery-based research.

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.