Tumor suppressor network dysregulation in neuroblastoma: molecular mechanisms and precision therapeutic opportunities.

Authors

Rohan Gupta, Sorabh Lakhanpal, Naveen Kumar, Rupak Nagraik, Karthikeyan Ravi, Shivanshu Sharma, Mosleh Mohammad Abomughaid, Smita Kumari, Niraj Kumar Jha

Published in

Frontiers in cell and developmental biology. Volume 14. Pages 1844582. Epub Jun 19, 2026.

Abstract

Neuroblastoma is the most common extracranial solid malignancy in children and accounts for nearly 15% of paediatric cancer-related mortality, underscoring its substantial clinical burden. Although multimodal therapeutic strategies, including chemotherapy, surgical resection, radiotherapy, stem cell transplantation, and immunotherapy, have improved outcomes in low- and intermediate-risk disease, survival rates for high-risk neuroblastoma remain poor due to frequent relapse and treatment resistance. While oncogenic drivers, such as MYCN amplification and ALK mutations have been extensively investigated, accumulating genomic and epigenomic evidence indicates that disruption of tumor suppressor gene (TSG) networks plays a central role in neuroblastoma pathogenesis. Unlike many adult malignancies driven by somatic mutations, neuroblastoma frequently exhibits tumor suppressor gene dysfunction through chromosomal deletions, copy number alterations, epigenetic silencing, and dysregulated signaling pathways. Major tumor suppressive pathways affected include Tp53-mediated apoptosis and genomic stability, RB-dependent cell cycle regulation, PTEN/PI3K/AKT survival signaling, Hippo pathway control of proliferation and stemness, and DNA damage response mechanisms. These interconnected networks drive tumor progression, metastatic dissemination, immune evasion, metabolic adaptation, and therapeutic resistance. Consequently, researchers are actively exploring therapeutic strategies targeting tumor suppressor-associated vulnerabilities. However, clinical translation remains challenging due to tumor heterogeneity, developmental toxicity concerns, and adaptive resistance mechanisms. This review summarizes the molecular mechanisms underlying tumor suppressor dysfunction in neuroblastoma and discusses emerging translational strategies targeting interconnected oncogenic, epigenetic, metabolic, and immune-associated signaling networks.

PMID:
42405329
Bibliographic data and abstract were imported from PubMed on 06 Jul 2026.

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