Gut. 2026 Sep 11:gutjnl-2026-338471. doi: 10.1136/gutjnl-2026-338471. Online ahead of print.
ABSTRACT
BACKGROUND: Liver cancer exhibits profound spatial and cellular heterogeneity, contributing to tumour progression, invasion and therapeutic resistance. Emerging evidence suggests that rare low-abundance malignant cell populations residing within discrete tissue niches influence these processes. However, their reliable detection and identification remain challenging due to the limitations of conventional spatial and single-cell transcriptomic analyses, which often rely on single-sample convergence and a lack of cross-cohort reproducibility.
OBJECTIVE: To develop a robust framework for identifying rare malignant cell populations across heterogeneous spatial transcriptomic datasets and to characterise their functional role in liver cancer progression.
DESIGN: We developed the Niche Cluster Atlas with Cellular Co-localisation (NCACC), a dual-layer framework integrating spatial organisation with cellular composition to enable cross-sample niche discovery. NCACC was applied to a comprehensive liver cancer transcriptomic atlas to identify rare niche-associated malignant cell populations.
RESULTS: NCACC stratified liver cancer tumour architecture into reproducible multicellular niche modules and enabled a tumour-invasive front-enriched rare cancer-derived IgG (cIgG)+ epithelial cell population. These cells enhanced proliferative and invasive characteristics and were associated with disease progression. Mechanistic analyses identified a STAT1-dependent cIgG-JAK-STAT signalling axis sustaining the invasive-front phenotype and promoting cIgG+ epithelial cell aggressive behaviours. We then combined structure-guided virtual screening with patient-derived organoid validation to identify nordihydroguaiaretic acid and gallic aldehyde as candidate modulators.
CONCLUSION: Our study establishes NCACC as a generalisable framework for high-confidence rare malignant cell identification across heterogeneous spatial transcriptomic cohorts, highlighting the cIgG-JAK-STAT as a therapeutically actionable driver of liver cancer invasion.
PMID:42728030 | DOI:10.1136/gutjnl-2026-338471