Nat Cancer. 2026 Jan 16. doi: 10.1038/s43018-025-01107-w. Online ahead of print.

ABSTRACT

The concept of cellular neighborhoods, defined as recurring structures within the tissue with characteristic cell compositions and interactions, has transformed our understanding of the complexity and dynamics of tumor ecosystems. Recent advances in spatial omics and computational modeling have enabled high-resolution mapping of these neighborhoods, providing unprecedented insights into their roles in shaping tumor heterogeneity, evolution and therapeutic responses. Despite these advances, a unified framework for interpreting cellular neighborhoods remains lacking. This Perspective synthesizes emerging concepts and insights, focusing on the definition and classification of cellular neighborhoods in cancer, computational methods for identifying and comparing them, and their clinical relevance.

PMID:41545713 | DOI:10.1038/s43018-025-01107-w

Front Immunol. 2025 Sep 19;16:1631708. doi: 10.3389/fimmu.2025.1631708. eCollection 2025.

ABSTRACT

This study investigates the role of ubiquitination-related genes in pancreatic cancer (PC) using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and multi-omics approaches. scRNA-seq data (GSE155698) from PC samples identified 12 cell types, with endothelial cells exhibiting high ubiquitination scores (High_ubiquitin-Endo) and enriched interactions with fibroblasts/macrophages via WNT, NOTCH, and integrin pathways. Spatial transcriptomics (GSE235315) validated cell-type localization. Mendelian randomization (SMR) analysis prioritized TRIM9 as a PC-protective gene, downregulated in tumors and correlated with better survival. WGCNA revealed TRIM9-co-expressed modules linked to prognosis. A machine learning-based prognostic model (CoxBoost+RSF) integrating seven genes (TSPAN6, TSC1, RNF167, PBXIP1, LRRC49, KATNAL2, IGF2BP2) stratified patients into high/low-risk groups with distinct survival, mutation burdens, and immune infiltration. TRIM9 overexpression suppressed PC cell proliferation/migration in vitro, while knockdown enhanced malignancy. Mechanistically, TRIM9 promoted K11-linked ubiquitination and proteasomal degradation of HNRNPU, dependent on its RING domain. In vivo, TRIM9 overexpression reduced tumor growth, rescued by HNRNPU co-expression. Integrated analyses highlight TRIM9 as a tumor suppressor and prognostic biomarker, mediated via ubiquitination-dependent regulation of HNRNPU stability. This work provides insights into ubiquitination-driven PC pathogenesis and therapeutic targeting.

PMID:41050689 | PMC:PMC12491318 | DOI:10.3389/fimmu.2025.1631708