Oncogenic function and transcriptional dynamics of MYCN in liver tumorigenesis
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (26)
Xian-Yang Qin
Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences
Yali Xu
State Key Laboratory of Drug Research
Hricha Mishra
Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences
Yohei Shirakami
Department of Gastroenterology, Graduate School of Medicine, Gifu University
Shiou-Hwei Yeh
Department of Microbiology, National Taiwan University College of Medicine
Chiao-Ling Li
Department of Microbiology, National Taiwan University College of Medicine
Kazushi Numata
Gastroenterological Center, Yokohama City University Medical Center
Yusuke Suenaga
Feifei Wei
Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute
Reiko Ando
Support Unit for Bio-Material Analysis, Research Resources Division, RIKEN Center for Brain Science
Hajime Nishimura
Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences
Erina Furuhata
Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences
Shiori Maeda
Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences
Yutaka Furutani
Department of Laboratory Medicine, The Jikei University School of Medicine
Kaori Yanaka
Department of Laboratory Medicine, The Jikei University School of Medicine
Masahiro Yamamoto
Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University
Masanori Goto
Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University
Akira Takasawa
Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University
Yuji Nishikawa
Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University
Hiroyuki Tomita
Department of Tumor Pathology, Gifu University Graduate School of Medicine
Luc Gailhouste
Laboratory for Brain Development and Disorders, RIKEN Center for Brain Science
Tomokazu Matsuura
Department of Laboratory Medicine, The Jikei University School of Medicine
Pei-Jer Chen
Graduate Institute of Clinical Medicine, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital
Masahito Shimizu
Department of Gastroenterology, Graduate School of Medicine, Gifu University
Yoshitaka Hippo
Laboratory of Evolutionary Oncology, Chiba Cancer Center Research Institute
Harukazu Suzuki
Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences