Spatial transcriptional features of MYCN niche in liver tumorigenesis.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, often diagnosed at advanced stages and characterized by high recurrence rates. While chronic liver inflammation and metabolic dysfunction are recognized contributors to tumorigenesis, the molecular mechanisms linking early microenvironmental stress to malignant transformation remain poorly understood. MYCN, a proto-oncogenic transcription factor, has emerged as a potential biomarker of cancer stemness, yet its functional role in hepatocarcinogenesis is unclear. Here, we elucidate the oncogenic role of MYCN and its dynamic regulation during metabolic liver tumorigenesis. Transcriptomic profiling revealed that MYCN-driven tumors exhibit features of human HCC subtypes enriched in stress-adaptive transcriptional programs. Time-resolved spatial transcriptomics further uncovered a MYCN-enriched niche characterized by epithelial–mesenchymal transition (EMT) and Wnt/ß-catenin signaling, which expanded during tumor progression and was spatially proximate to transformed malignant cells. Overall design: Spatial transcriptomics using the 10× Genomics Visium platform in a metabolic HCC mouse model STAM (STAM16w, STAM20w), which mimics MASH and type I diabetes, and in a fibrotic HCC mouse model DEN+CCL4 (DEN22w, DEN30w), which mimics DNA damage–driven and fibrosis-promoting tumor evolution.