The human genome encodes ~1,900 secreted proteins, many of which mediate intercellular communication. Secreted proteins do not act cell-autonomously, limiting systematic approaches to characterize their functions. Here we introduce SecAct (Secreted Activity, https://secact.ccr.cancer.gov ), a computational framework that infers the signaling activities of 1,170 human secreted proteins from spatial, single-cell and bulk transcriptomic data. The inference model harnesses precomputed intercellular signaling signatures trained on 1,258 spatial transcriptomics samples spanning 37 cancer types. Transcriptomics data from antisecreted protein therapies validate SecAct's accuracy in predicting the repression of secreted protein activity following treatment. For spatial and single-cell transcriptomics data, SecAct provides interactive modules for analyzing secreted protein-mediated cell-cell communication. Applying SecAct to 54 cancer immunotherapy cohorts comprising 5,174 patients, we identified secreted proteins associated with tumor immunity. In vivo experiments validated lymphocyte antigen 86 (LY86), whose function in cancer was previously unknown, as an antitumor regulator.

The acidic tumor microenvironment (TME) is a major driver of immunosuppression and tumor progression in breast cancer. Although myosin VI (MYO6), an actin-dependent motor protein, is frequently upregulated in malignancies, its function in immune remodeling remains poorly understood.

Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder characterized by significant reproductive and metabolic complications. Insulin resistance (IR) plays a central role in the pathophysiology of PCOS and contributes to several associated metabolic abnormalities. This review highlights the key mechanisms underlying PCOS, including IR, hyperandrogenism, cardiovascular disease, gut microbiota dysbiosis, and the increased risk of type 2 diabetes mellitus (T2DM), along with current and emerging therapeutic strategies for improving disease outcomes. Accumulating evidence suggests that genetic predisposition contributes to PCOS susceptibility. Polymorphisms in genes such as the androgen receptor (AR), cytochrome P450 17A1 (CYP17), and follicle-stimulating hormone receptor (FSHR) have been associated with altered steroidogenesis and ovarian dysfunction, thereby influencing disease severity. In addition to genetic factors, environmental influences, including exposure to endocrine-disrupting chemicals (EDCs) and air pollution, may exacerbate metabolic disturbances and increase the risk of developing PCOS. Conventional therapeutic approaches focus on improving insulin sensitivity and correcting hormonal imbalances. These include pharmacological treatments such as metformin, oral contraceptives, and lifestyle modifications involving diet and physical activity. Recently, novel therapeutic strategies have emerged, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), microRNA-based therapies, and interleukin-22 (IL-22)-mediated interventions, which show potential in targeting IR and metabolic dysfunction in PCOS. Furthermore, modulation of gut microbiota through probiotics, prebiotics, and fecal microbiota transplantation (FMT) represents an emerging strategy for restoring metabolic homeostasis. Overall, a comprehensive and personalized therapeutic approach integrating pharmacological, lifestyle, and microbiome-targeted interventions may significantly improve PCOS management and reduce long-term metabolic and reproductive complications.

IntroductionDysregulated epidermal growth factor receptor (EGFR) signaling is a key mechanism driving cancer progression and metastasis. Owing to its frequent overexpression in pancreatic cancer (PCa), EGFR has become a desirable molecular target for targeted therapies. XYZ-I-73 (N-(5-fluoro-2-oxo-1-(tetrahydrofuran-2-yl)-1,2-dihydropyrimidin-4-yl) dodecanamide), a structural analog of 5-fluorouracil (5-FU), has been previously synthesized and shown to exhibit cytotoxicity against PCa cells.MethodsXYZ-I-73 was entrapped in liposomes via thin-film hydration and subsequently conjugated to EGFR antibodies to produce an immunoliposome formulation- Ab-XYZ-I-73LnP (where 'Ab' denotes antibody-conjugated and 'LnP' denotes liposomal nanoparticle). In vitro efficacy was assessed by measuring cell viability and apoptosis in MiaPaCa-2 and PANC-1 cells, while pharmacokinetics and antitumor efficacy were determined in a cell line-derived xenograft (CDX) mouse model.ResultsAb-XYZ-I-73LnP exhibited a mean particle size of 143nm ± 2.3, PDI (0.37), and zeta potential -46.2 ± 1.3mV. In MiaPaCa-2 cells, Ab-XYZ-I-73LnP showed remarkably higher cytotoxicity than 5-FU in both 2D (IC50 = 2.5 ± 0.9μM vs 13.2 ± 1.1μM) and 3D cultures (IC50 = 8.1 ± 1.1μM vs 26.7 ± 1.1 μM). Similarly, in PANC-1 cells, Ab-XYZ-I-73LnP showed lower IC50 values compared to 5-FU;2D (IC50 = 2.9 ±1.1 μM vs 20.4±1.2 μM), 3D (IC50 = 12.9 ± 0.6μΜ vs 37.1±0.9 μM). Pharmacokinetic analysis revealed a prolonged half-life for Ab-XYZ-I-73LnP compared with free 5-FU (t1/2 = 1.62 ± 0.03 h vs 0.49 ± 0.01 h, p < 0.001). There was about a 2-fold increase in the area under the curve (AUC) for Ab-XYZ-I-73LnP compared to 5-FU (AUC= 0.32 ± 0.04µg/(L*hr) vs 0.15 ± 0.02µg/(L*hr), p<0.01).ConclusionOverall, the study supports the formulation of an immunoliposome of modified 5-FU, which may significantly enhance drug bioavailability and therapeutic potential for the treatment of PCa.

The mechanisms underlying the interactions between disseminated tumor cells (DTCs) and their tissue microenvironment during metastatic colonization are currently poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments from single-cell seeding to overt lung metastasis. We identified a residual population of quiescent Phgdhhigh DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases. These cells shaped an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, thereby promoting metastatic expansion. Cx3cr1high interstitial macrophages were also transiently enriched before DTC expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the PHGDH-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide insights into the development of micrometastasis-targeting regimens.

More than 600,000 cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed globally each year. Many HNSCCs overexpress the ERBB family member epidermal growth factor receptor (EGFR), and EGFR inhibitors (EGFRi) and pan-ERBB inhibitors (ERBBi) are clinically active in the treatment of locally advanced, metastatic, or recurrent HNSCC. However, resistance to these inhibitors typically develops, often associated with epithelial-mesenchymal transition (EMT). Aurora kinase A (AURKA), a mitotic regulator with expanded signaling functions in tumors, has been reported to reverse EGFR resistance in EGFR-mutated lung cancer. To identify strategies to overcome resistance in HNSCC, we developed HNSCC cell models that were treatment-naïve parental or selected for resistance to the EGFRi erlotinib or the ERBBi afatinib. The resistant HNSCC models had typically undergone partial EMT, consistent with clinical resistance, associated with upregulation of the AURKA partner protein NEDD9. Synergy of the AURKA inhibitor VIC-1911 with erlotinib or afatinib in parental models was reduced in resistant models in short-term growth assays. In longer-term clonogenic assays and in vivo, cells selected for EGFRi/ERBBi resistance showed heightened sensitivity to VIC-1911, contributing to reduced synergy. Based on increased AURKA dependence, we compared the combination of VIC-1911 with adavosertib, an inhibitor of the cell-cycle checkpoint regulator WEE1, in parental and resistant models. These showed a combination effect both in vitro and in vivo that was retained in ERBBi-resistant xenografts, suggesting the potential value of combined AURKA and WEE1 inhibitor use in patients with ERBBi-resistant HNSCC.

The treatment of non-small cell lung cancer (NSCLC) has challenges such as drug resistance and recurrence. Concurrently, the induction of apoptosis and ferroptosis is a promising therapeutic strategy. This study aimed to investigate whether the natural product, verbascoside, induces apoptosis and ferroptosis in NSCLC cells by targeting BCAT2.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, driven by late-stage diagnosis, metastatic progression, and therapeutic resistance. Src homology region 2 domain-containing phosphatase 2 (SHP2) has emerged as a critical regulator of oncogenic signaling in gastric tumorigenesis, yet its therapeutic targeting remains underexplored. In this study, we evaluated the anti-cancer efficacy of NSC 57774, a novel SHP2 inhibitor, using integrated bioinformatics and functional assays in AGS gastric cancer cells. Analysis of The Cancer Genome Atlas (TCGA) and UALCAN datasets revealed marked upregulation of SHP2 and multiple receptor tyrosine kinases in gastric cancer tissues. NSC 57774 potently inhibited cell proliferation and migration, demonstrating selective cytotoxicity towards cancer cells over non-cancerous fibroblasts. Mechanistically, NSC 57774 disrupted key oncogenic pathways including MAPK/ERK, AKT and STAT3 in a concentration- and time-dependent manner, with higher doses achieving more sustained pathway suppression. NSC 57774 suppressed NF-κB inflammatory signaling at early timepoints and induced cleaved caspase-3 across all treatment groups at 72 hours, indicative of pro-apoptotic activity. A paradoxical late-phase increase in phospho-p38 was observed at 72 hours, consistent with a compensatory pro-apoptotic stress response. Comparative analysis revealed that NSC 57774 outperformed the commercial SHP2 inhibitor NSC 87877 and doxorubicin in reducing viability and migration of gastric cancer cells. Collectively, these findings position NSC 57774 as a promising candidate for targeted gastric cancer therapy, capable of disrupting multiple signaling pathways involved in tumor progression, metastasis, and inflammation, warranting further preclinical and clinical investigation.

Pathogenic variants in BRCA1 and BRCA2 confer substantial risks of breast and ovarian cancer; however, risk for female individuals undergoing testing, particularly those with variants of uncertain significance (VUS) or negative results, remain poorly defined.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with tumor-associated macrophages (TAMs), predominantly M2-polarized, shaping a tumor-promoting microenvironment. ETS proto-oncogene 2 (ETS2) is aberrantly upregulated in CRC, but its role in exosome-mediated intercellular communication and TAM polarization remains unclear. Here, public datasets and single-cell RNA sequencing were analyzed to characterize ETS2 expression and cellular distribution in CRC. Co-culture of THP-1-derived M0 macrophages with CRC cells (LoVo and HCT-116), combined with isolation of tumor-derived exosomes, was used to assess exosome-mediated ETS2 transfer and macrophage M2 polarization. CRC cell proliferation, migration, apoptosis, CD8⁺ T cell apoptosis, and macrophage M2 polarization were evaluated by CCK-8, EdU incorporation, flow cytometry, RT-qPCR, and Transwell assays. Chromatin immunoprecipitation and dual-luciferase reporter assays confirmed transcriptional activation of pre-mRNA processing factor 4 (PRPF4) by ETS2, and a xenograft mouse model was used to assess in vivo effects. ETS2 expression was elevated in CRC tissues and TAMs and correlated positively with M2 polarization. Silencing ETS2 inhibited CRC cell proliferation and migration, promoted apoptosis, reduced macrophage M2 polarization, and decreased CD8⁺ T cell apoptosis. Mechanistically, ETS2 activated PRPF4 transcription, and PRPF4 overexpression reversed the inhibitory effects of ETS2 knockdown. CRC-derived exosomes mediated ETS2 transfer to macrophages, promoting M2 polarization, and in vivo PRPF4 overexpression significantly rescued tumor growth suppressed by ETS2 knockdown. These findings indicate that exosomal ETS2 promotes CRC progression and M2 macrophage polarization via PRPF4, highlighting the ETS2/PRPF4 axis as a potential therapeutic target.

Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are characterized by recurrent MDM2-centered amplification of chromosome 12q13-15, yet this diagnostic label reduces a complex structural lesion to a binary result. An architecture-resolved 12q amplicon platform requires an MDM2-centered dosage anchor plus direct evidence of nontrivial topology or carrier state; cargo, regulatory, and functional data define progressively higher-resolution features. When only MDM2 amplification is documented, the lesion is best described as diagnostic 12q amplification rather than a fully resolved platform. This review presents an evidence-graded architecture-to-function framework that separates direct WDLPS/DDLPS observations from mechanisms inferred from broader amplification biology. Disease-specific evidence supports heterogeneous 12q carriers, including ring, giant marker, rod-shaped, discontinuous, and neochromosome-like structures, as well as enhancer coamplification or altered 3D contacts. In contrast, chromothripsis, telomere crisis/BFB remodeling, ecDNA-like dynamics, and enhancer hubs are treated as extrapolated or testable mechanisms unless directly validated in liposarcoma. Conclusions are weighted by methodological resolution: cytogenetics/FISH define diagnostic amplification and visible carrier classes; MLPA or array-based assays define dosage and discontinuity; WGS with long-read or optical mapping is needed for junction-level architecture; and single-cell/spatial assays mainly resolve cellular-state or ecosystem context unless paired with structural readouts. MDM2-p53 and CDK4-RB remain central outputs, whereas selected cargo, lineage state, metabolism, and tumor-microenvironment programs are interpreted as evidence-ranked cooperating or downstream modules. Clinically, architecture-aware interpretation is proposed as a prospective framework for sampling, model design, biomarker development, and trial stratification, not as an established basis for routine management.

Fibroadenoma is the most common benign fibroepithelial lesion of the breast; it occurs most frequently in adolescents and women of reproductive age. While fibroadenoma is considered a non-invasive lesion with a good prognosis, some fibroadenomas may show rapid growth, recurrence, stromal hypercellularity, epithelial proliferative changes and even show radiological overlap with phyllodes tumour and breast carcinoma resulting in significant diagnostic dilemmas. In recent years, molecular pathology and biomarker studies have led to better understanding of the biology of fibroadenomas, and their ability to differentiate between fibroadenomas and malignant breast lesions. This review will provide a comprehensive overview of biomarkers involved in the diagnosis, prognosis, prediction, molecular, genetic, epigenetic, functional, circulating and imaging of breast fibroadenoma and breast cancer. The key biomarkers such as MED12 mutation, Ki-67, p53, Bcl-2, ER/PR, HER2, VEGF, MMPs, γ-H2AX, ctDNA, circulating tumour cells and transcriptomic classifiers are discussed in the context of tumour proliferation, apoptosis, angiogenesis, invasion, genomic instability and malignant transformation risk. The retrieved relevant literature was from 2000 to 2025 from the databases of PubMed, Scopus, Web of Science, and Google Scholar. The review further emphasizes the growing significance of liquid biopsy, radiomics, artificial intelligence, digital pathology, and the integration of multi-omics techniques for enhancing lesion classification, diagnostic accuracy, and personalized risk assessment. Many challenges still exist such as a lack of standardised cut off values for biomarkers, overlap between fibroadenoma and phyllodes tumour, a lack of molecular panels specifically designed for fibroadenoma and a lack of long-term validation studies. Further incorporation of molecular profiling, imaging biomarkers, computational pathology, and precision oncology approaches into the future could greatly enhance the risk stratification and handling of benign and malignant fibroepithelial breast lesions.

Treatment choices for metastatic non-small-cell lung cancer (NSCLC) after first-line targeted therapy progression are heterogeneous. This study aimed to characterize real-world treatment patterns and outcomes of advanced NSCLC harboring actionable genomic alterations (AGAs) in second- (2 L) or third-line (3 L) settings. This retrospective cohort study across six Chinese centers included stage IV NSCLC patients with confirmed AGAs. Therapies were divided into six categories: targeted monotherapy (T), targeted combinations (T+), chemotherapy monotherapy (C), chemotherapy combinations (C+), anti-angiogenic monotherapy (A), and other regimens (O). The primary outcome was the treatment pattern. Secondary outcomes included biomarker testing and effectiveness. A total of 658 patients were enrolled, with the majority harboring EGFR mutations (n = 590, 89.7%). In the 2 L-enrolled group (n = 602), T use declined from 75.3% in the 1 L setting to 49.3% in 2 L, while utilization of A + C increased to 16.5%. Within the EGFR-mutant subgroup, therapeutic sequences were highly dependent on 1 L TKI generation and T790M resistance status. Over half (51.1%) of T790M-negative patients continued T in 2 L following progression on 1 L first- or second-generation TKIs. Among the 3 L-enrolled patients (n = 56), A + C (35.7%) and C (14.3%) were predominant. The overall median real-world progression-free survival for the 2 L-enrolled group was 7.4 months in the 2 L setting (7.5 months for the EGFR-mutant subgroup) and 5.4 months in 3 L. This multicenter real‑world cohort predominantly comprised patients with EGFR‑mutant NSCLC, with smaller numbers of other AGA subtypes. Targeted therapies remain the cornerstone of later-line advanced NSCLC management. The prevalent real-world reliance on continued TKI therapy, even in T790M-negative patients, highlights the clinical dilemma of limited post-resistance options and the need to integrate emerging novel therapeutics.

Breast cancer (BC) is the most commonly diagnosed malignant disease in women worldwide. Resistance to neoadjuvant chemotherapy (NAC) still limits treatment efficacy despite the enormous progress in systemic therapy. Because pathological complete response (pCR) is strongly associated with favorable clinical outcomes, especially in triple-negative and HER2-positive breast cancer, the discovery of reliable predictive biomarkers before treatment has become a key clinical goal. This narrative review summarizes the available evidence of genetic and transcriptomic biomarkers associated to responses to conventional anthracycline, taxane and platinum-based NAC. Current evidence suggests biomarkers can be broken down into three interconnected biological pathways. Dysregulation of immune and interferon signaling, including interferon-stimulated genes (ISG15, IFIH1, MX1, OAS family, IFI27, and IFITM1), affects chemotherapy response by modulating immune activation, apoptosis, and DNA damage tolerance. Second, alterations in DNA damage response (DDR) pathways for BRCA1, TP53, PARP1, ATM, and CHK1 affect the cells' vulnerability to genotoxic stress and contribute to the subtype-specific differences in treatment efficacies. Third, dysregulated cell cycle components (CCND1, CDK4/6, RB1, and E2F1) affect proliferation, checkpoint control, and susceptibility to chemotherapy-induced apoptosis. These pathways act in concert, rather than as independent mechanisms, to influence NAC sensitivity. Available data suggest that no single biomarker has sufficient predictive accuracy for all breast cancer subtypes. Subtype-specific multi-gene models integrating immune, DDR and cell-cycle biomarkers represent a more powerful tool to predict pCR and improve patient stratification before NAC. Further prospective clinical validation is needed before these biomarkers can be implemented in routine clinical practice.

To evaluate the proportion of expressed programmed cell death ligands-1 (PD-L1) in epithelial ovarian carcinoma patients, and the association with the clinicopathological, surgical outcomes, and oncologic outcomes. To compare PD-L1 protein expression with messenger ribonucleic acid (mRNA) expression.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown limited efficacy in gastric cancer, primarily due to the rarity of inherent homologous recombination (HR) deficiency. The nuclear Arp2/3 complex was recently implicated in DNA double-strand break repair via HR. Here, we investigate whether pharmacological inhibition of Arp2/3 can induce a functional HR-deficient state to synergize with PARPi in gastric cancer cells.

Recent research has identified pyroptosis as a distinct form of programmed cell death that is strongly correlated with tumor outcomes. However, its value as a prognostic biomarker in clear cell renal cell carcinoma (ccRCC) is not yet fully established.

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide; thus, understanding its molecular mechanisms is critical for developing novel therapeutic targets. Long non-coding RNAs (lncRNAs) play crucial isoform-specific roles in cancer. While oncogenic lncRNA LINC00673 is known to be involved in multiple malignancies and possesses five distinct transcript variants, the functional role of LINC00673-V4-a highly expressed transcript variant in CRC-remains largely unexplored. This study investigated how LINC00673-V4 drives CRC proliferation by modulating the Hippo-Yes-associated protein (Hippo-YAP) signaling pathway.

Accurate identification of actionable somatic variants is essential for therapeutic stratification in colorectal cancer (CRC). While next-generation sequencing (NGS) enables comprehensive genomic profiling, targeted approaches may provide faster and more practical alternatives for routine diagnostics.

Cervical cancer (CC) is a prevalent malignancy in women. RNA-binding motif single-stranded interacting protein 3 (RBMS3) acts as a tumor suppressor in many cancer types, but its role and underlying regulatory mechanisms in CC remain unclear.