Transl Oncol. 2026 Apr 3;67:102748. doi: 10.1016/j.tranon.2026.102748. Online ahead of print.

ABSTRACT

BACKGROUND: Epithelial ovarian cancer (EOC) encompasses five major histological subtypes with marked genetic, immunological, and clinical heterogeneity. While genome-wide association studies (GWAS) have identified subtype-specific risk loci, a critical gap remains in understanding how plasma proteins influence immune-cell traits and contribute to EOC pathogenesis.

METHODS: We integrated subtype-stratified GWAS data from two EOC cohorts with plasma proteomics and immune-cell traits to construct protein-immune-EOC regulatory landscapes using a three-stage Mendelian randomization framework. Single-cell RNA-seq and multiplex immunofluorescence were employed to delineate the cellular distribution and spatial context of causal proteins. Subsequent analyses characterized immune infiltration, macrophage polarization, and clinicopathological associations. Drug-gene correlations were used to identify potential therapeutic targets, and transcriptomic analyses were applied to delineate the underlying transcriptional landscape.

RESULTS: We identified 20 subtype-specific protein-immune-EOC regulatory axes, with FCGR2B emerging as a causal plasma protein in immune regulation and high-grade serous ovarian cancer (HGSOC) progression. FCGR2B was highly expressed in tumor-associated macrophages and was associated with an M2-like polarization phenotype. Functional characterization revealed that FCGR2B was associated with shorter progression-free survival and an immunosuppressive tumor microenvironment. Transcriptomic analyses revealed altered NF-κB signaling upon FCGR2B knockdown, and drug-response data suggested a potential association between high FCGR2B expression and sensitivity to NF-κB inhibitors.

CONCLUSIONS: These findings delineate subtype-specific genetically informed protein-immune regulatory landscapes in EOC and identify FCGR2B as a key immunoregulatory and prognostic biomarker in HGSOC, suggesting FCGR2B as a potential therapeutic vulnerability that warrants further investigation.

PMID:41934917 | DOI:10.1016/j.tranon.2026.102748

Adv Sci (Weinh). 2026 Apr 3:e17640. doi: 10.1002/advs.202517640. Online ahead of print.

ABSTRACT

The embryonic coelomic mesothelium acts as a critical progenitor hub during mammalian organogenesis, undergoing epithelial-to-mesenchymal transition (EMT) to drive vascular growth and parenchymal development in visceral organs. A prominent example is the epicardium, which plays an essential role during heart development. The principles of gene regulation in the coelomic mesothelium remain poorly defined. Specifically, it is unclear how cis-regulatory elements, including enhancers, orchestrate the spatiotemporal patterns of gene expression required for mesothelial identity and function. Here, a multi-omic approach was used to identify trans- and cis-regulatory elements that regulate mesothelial gene expression in three organs: heart, lung, and pancreas. This analysis uncovers a cardiac-specific regulatory circuit in which the transcription factor (TF) TBX20 selectively activates epicardial enhancers to orchestrate essential developmental programs. In contrast, TF MAF orchestrates pan-mesothelial gene expression via conserved CREs, which are absent in non-mesothelial lineages. Our integrated genomic analysis reveals MAF as a central custodian of mesothelial identity, a role underscored by its negative correlation with EMT, evolutionary conservation, and dynamic regulatory activity throughout development. Our work establishes a foundational blueprint of the gene regulatory landscape governing the coelomic mesothelium, defining both conserved principles and organ-specific mechanisms of spatiotemporal gene expression during early mammalian development.

PMID:41933934 | DOI:10.1002/advs.202517640