Mol Omics. 2025 Oct 1. doi: 10.1039/d5mo00221d. Online ahead of print.

ABSTRACT

BACKGROUND: cancer exhibits high molecular and clinical heterogeneity, making accurate subtyping essential for personalized treatment. Traditional single-omics approaches often fail to capture this complexity. Multi-omics integration offers a more holistic understanding, but many existing methods either lack interpretability or fail to model cross-omics correlations effectively.

METHODS: we developed MOFNet, a novel supervised deep learning framework for multi-omics integration, incorporating a similarity graph pooling (SGO) module and a view correlation discovery network (VCDN). MOFNet processes omics data-including mRNA expression, DNA methylation, and miRNA expression-via omics-specific graph learning and cross-omics label space fusion. Three cancer types-breast cancer (BRCA), low-grade glioma (LGG), and stomach adenocarcinoma (STAD)-were analyzed using datasets from the cancer genome atlas (TCGA). Statistical evaluation was performed using accuracy, weighted F1 score, and macro F1 score across stratified training/testing splits.

RESULTS: MOFNet achieved superior performance across all datasets. For BRCA, it obtained an accuracy of 85.17%, F1_weighted of 85.36%, and macro F1 of 80.93%, outperforming all baseline models by up to 18.25%. In LGG and STAD, MOFNet also showed robust gains, with maximum improvements of 23.72% and 21.56%, respectively. Omics ablation studies demonstrated enhanced performance with multi-omics integration. Functional enrichment analysis revealed that MOFNet-identified key features were involved in biologically relevant pathways such as cell cycle regulation, synaptic signaling, and ion transport.

CONCLUSIONS: MOFNet enables scalable and interpretable multi-omics data fusion for cancer subtype classification, significantly improving predictive accuracy while retaining only 25% of input features. The integration of SGO and VCDN modules offers both biological interpretability and computational efficiency. These results suggest MOFNet's promising application in precision oncology and biomarker discovery.

PMID:41031935 | DOI:10.1039/d5mo00221d

Nat Rev Clin Oncol. 2025 Oct 3. doi: 10.1038/s41571-025-01077-z. Online ahead of print.

ABSTRACT

Patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) predominantly receive chemotherapy, and despite initial responses in some patients, most will have disease progression and often dismal outcomes. This lack of clinical effectiveness partly reflects not only cancer cell-intrinsic factors but also the presence of a tumour microenvironment (TME) that precludes access of both systemic therapies and circulating immune cells to the primary tumour, as well as supporting the growth of PDAC cells. Combined with improved preclinical models of PDAC, advances in single-cell spatial multi-omics and machine learning-based models have provided novel methods of untangling the complexities of the TME. In this Review, we focus on the desmoplastic stroma and both the intratumoural and intertumoural heterogeneity of PDAC, with an emphasis on cancer-associated fibroblasts and their surrounding immune cell niches. We describe new approaches in converting the immunologically 'cold' PDAC TME into a 'hot' TME by priming T cell activation, overcoming T cell exhaustion and unravelling myeloid cell-mediated immunosuppression. Furthermore, we explore integrated targets involving the TME, such as points of convergence among tumour, stromal and immune cell metabolism as well as oncogenic KRAS signalling. Finally, building on our experience with failed clinical trials in the past, we consider how this evolving comprehensive understanding of the TME will ensure future success in developing more effective therapies for patients with PDAC.

PMID:41044427 | DOI:10.1038/s41571-025-01077-z

Front Immunol. 2025 Sep 12;16:1638445. doi: 10.3389/fimmu.2025.1638445. eCollection 2025.

ABSTRACT

BACKGROUND: Air pollution may crosstalk with immune system to promote hepatocellular carcinoma (HCC) development, but its precise mechanisms and prognostic significance remain unclear.

OBJECTIVE: This study aims to construct a prognostic signature for HCC based on air pollutant-related immune genes (APIGs).

METHODS: We obtained mRNA-seq and scRNA of HCC from GEO, TCGA and ICGC. AP-related target genes were retrieved from several online databases. APIGs were obtained using WGCNA, differential gene expression analysis and immune infiltration analysis. Molecular subtypes were conducted based on APIG expression to characterize immune features. A total of 101 combinations of 10 machine learning algorithms were used to construct an APIG-based prognostic signature (APIGPS). Furthermore, we performed qRT-PCR, survival analyses, functional enrichment, immune infiltration and single-cell analyses. Subsequently, LASSO, RF, and RFE-SVM were employed to identify diagnostic genes, followed by pan-cancer analysis.

RESULTS: We identified 19 APIGs. HCC samples were divided into 3 subtypes, with C1 exhibiting a pro-tumor immune microenvironment and poorer prognosis. APIGPS constructed by 7 APIGs (CDC25C, MELK, ATG4B, SLC2A1, CDC25B, APEX1, GLS), demonstrated robust predictive ability independent of clinical features. The biological pathway differences between APIGPS-based high- and low-risk groups involved immune responses and cell proliferation and migration. APIGPS genes had stable binding to 7 APs and were mainly expressed in macrophages, with HRG exhibiting higher macrophage abundance. CDC25C was identified as the hub gene after intersecting diagnostic genes and APIGPS genes. CDC25C was associated with survival of 10 cancers, MSI in 10 cancers, TMB in 21 cancers, and immune cell abundance in 13 cancers.

CONCLUSIONS: We identified key APIGs and constructed a robust APIG-based prognostic signature for HCC. CDC25C was a key target through which APs impact HCC and multiple other cancers.

PMID:41019083 | PMC:PMC12463942 | DOI:10.3389/fimmu.2025.1638445

Biomedicines. 2025 Sep 11;13(9):2238. doi: 10.3390/biomedicines13092238.

ABSTRACT

Background:HTR1F (5-Hydroxytryptamine Receptor 1F) encodes a G protein-coupled receptor involved in serotonin signaling. Although dysregulated HTR1F expression has been implicated in certain malignancies, its biological functions and clinical significance across cancer types remain largely unexplored. Methods: We performed an integrative pan-cancer analysis of transcriptomic and pharmacogenomic datasets covering 34 cancer types (PAN-CAN cohort, N = 19,131; normal tissues, G = 60,499). Drug sensitivity and molecular docking analyses were conducted using the GSCALite database. The protein-protein interaction (PPI) network of HTR1F was constructed via the STRING database. Additionally, we evaluated the effects of HTR1F overexpression on proliferation and invasion in human lung squamous cell carcinoma (LUSC) cell lines NCI-H520 and NCI-H226. Results:HTR1F expression was significantly upregulated in 17 cancer types and was associated with poor prognosis, with LUSC showing an AUC of 0.912 for 1-year survival prediction. In LUSC, 695 genes were upregulated and 67 downregulated in response to HTR1F overexpression. HTR1F expression correlated with immune-related genes, immune checkpoints, tumor-infiltrating immune cells, tumor mutation burden (TMB), microsatellite instability (MSI), and drug responses. Genomic alterations, including amplification and deletion, were positively associated with HTR1F expression. Drug sensitivity analysis identified compounds such as sotrastaurin (-10.2 kcal/mol), austocystin D (-9.7 kcal/mol), and tivozanib (-9.3 kcal/mol) as potentially effective inhibitors based on predicted binding affinity. Functional enrichment analyses (GO, KEGG) and GSEA revealed that HTR1F is primarily involved in cell cycle regulation, DNA replication, cellular senescence, and immune-related pathways. Functional validation showed that HTR1F overexpression promotes proliferation of LUSC cells via the MAPK signaling pathway. Conclusions: Our integrative analysis highlights HTR1F as a potential biomarker associated with prognosis, immune modulation, and drug sensitivity across multiple cancer types. These findings provide a foundation for future experimental and clinical studies to explore HTR1F-targeted therapies.

PMID:41007799 | PMC:PMC12467612 | DOI:10.3390/biomedicines13092238

bioRxiv [Preprint]. 2025 Sep 17:2025.09.12.675904. doi: 10.1101/2025.09.12.675904.

ABSTRACT

Spatial 'omics technologies are a powerful tool for mapping the relationship between cellular organization and molecular distributions in healthy and diseased tissue microenvironments. Here, we describe a novel multimodal pipeline that represents experimental and computational advances for spatiomolecular analysis of tissue samples across molecular classes. This adaptable method integrates matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) lipidomics, spatial transcriptomics (ST), multiplexed immunofluorescence microscopy (MxIF), and histopathological staining to uncover spatiomolecular profiles associated with unique cellular niches and pathological features. We demonstrate the power of this approach using two different complex human disease systems: Alzheimer's disease in human brain tissue and type 2 diabetes mellitus in the human pancreas. By identifying molecular markers associated with disease pathology in the pancreas and brain, we shed light on biologically significant pathways that are impacted in these two spatially complex diseases and highlight the powerful potential of accurate, high-resolution multimodal integration approaches.

PMID:41000710 | PMC:PMC12458195 | DOI:10.1101/2025.09.12.675904

Nat Commun. 2025 Sep 25;16(1):8388. doi: 10.1038/s41467-025-63050-9.

ABSTRACT

Spatial technologies examining the cell and tissue microenvironment at near single-cell resolution are revealing important molecular insights. However, few tools enable integrated, interactive analysis of spatial-omics with tissue morphology in the same functional tissue unit. Here, we present FUSION (Functional Unit State Identification in Whole Slide Images), a web-based platform for visualizing and analyzing spatial-omics data with high-resolution histology. FUSION provides workflows for assessing cell compositions, quantitative morphometrics, and comparative tissue analyses. We demonstrate applicability across spatial assays, including 10x Visium, Visium HD, 10x Xenium, Cell DIVE, and PhenoCycler, applied to healthy and diseased tissues from kidney, small intestine, lung, and skin in the Human BioMolecular Atlas Program. FUSION is cloud-based, open-source, and accessible at https://fusion.hubmapconsortium.org/ , hosting over 50 paired datasets and tutorials. In a series of use cases, we show its capacity to distinguish renal glomeruli injury states, quantify morphometric changes, and characterize fibrosis with immune infiltration.

PMID:40998789 | PMC:PMC12462499 | DOI:10.1038/s41467-025-63050-9