2026-02-24 理化学研究所,千葉県がんセンター,岐阜大学,東京慈恵会医科大学
研究概念図
<関連情報>
- https://www.riken.jp/press/2026/20260218_2/index.html
- https://www.pnas.org/doi/10.1073/pnas.2521923123
肝腫瘍形成におけるMYCNの発癌機能と転写ダイナミクス Oncogenic function and transcriptional dynamics of MYCN in liver tumorigenesis
Xian-Yang Qin, Yali Xu, Hricha Mishra, +22 , and Harukazu Suzuki
Proceedings of the National Academy of Sciences Published:February 18, 2026
Significance
Hepatocellular carcinoma (HCC) remains a lethal cancer due to late diagnosis and frequent recurrence. Although MYCN is recognized as a stemness-associated oncogene, its role and spatial dynamics in liver tumorigenesis remain unclear. Here, we show that MYCN actively drives HCC development in combination with AKT activation and marks a spatially restricted microenvironment enriched for epithelial–mesenchymal transition (EMT) and Wnt/β-catenin signaling features that expand during tumor progression. Integrating spatial transcriptomics with machine learning, we develop a MYCN niche score that predicts recurrence risk and identifies precancerous microenvironments in nontumor liver tissue. This approach provides a potential strategy for early detection of high-risk patients before malignant transformation.
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. It is often diagnosed at advanced stages and characterized by high recurrence rates. Although chronic liver inflammation and metabolic dysfunction are established contributors to tumorigenesis, the molecular mechanisms that link microenvironmental stress to malignant transformation remain poorly understood. MYCN, a proto-oncogenic transcription factor, has emerged as a potential biomarker of cancer stemness. However, its role in hepatocarcinogenesis remains unclear. In this study, we elucidated the oncogenic role of MYCN and its dynamic transcriptional regulation during liver tumorigenesis. Using a hydrodynamic tail vein injection-based transposon system in mice, we demonstrated that MYCN overexpression synergizes with AKT activation to promote liver tumorigenesis. Transcriptomic profiling revealed that MYCN-driven tumors exhibited 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/β-catenin signaling, which expanded during tumor progression and was spatially proximate to transformed malignant cells. To translate these findings to human HCC, we developed a machine learning-based MYCN niche score and validated its clinical relevance across multiple human HCC cohorts. This score reliably predicted recurrence risk and identified EMT-prone microenvironments, with stronger predictive performance in nontumor tissues, suggesting its potential in detecting precancerous niches predisposed to de novo tumorigenesis. Collectively, our findings establish MYCN as a functional driver and spatial marker of tumor-promoting microenvironments in liver tumorigenesis; additionally, we propose a clinically actionable strategy to identify high-risk patients through transcriptomic profiling of nontumor liver tissue.
