Tumor suppressor network dysregulation in neuroblastoma: molecular mechanisms and precision therapeutic opportunities
Rohan Gupta1, Sorabh Lakhanpal2, Naveen Kumar3
1Department of Biotechnology and Bioengineering, School of Biosciences and Technology, Galgotias University, Greater Noida, Uttar Pradesh, India.
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.
Insights
Neuroblastoma, a common childhood cancer, has poor survival for high-risk cases. Disruptions in tumor suppressor gene networks, not just oncogenes, drive its progression and resistance to therapy.
Area of Science:
- Pediatric Oncology
- Cancer Genomics
- Molecular Mechanisms of Disease
Background:
- Neuroblastoma is the most common pediatric extracranial solid tumor and a leading cause of cancer death in children.
- While treatments improve outcomes for low- and intermediate-risk neuroblastoma, high-risk disease survival remains poor due to relapse and resistance.
- Tumor suppressor gene (TSG) network disruption is increasingly recognized as a key driver in neuroblastoma pathogenesis, distinct from typical adult cancer mutations.
Purpose of the Study:
- To review the molecular mechanisms of tumor suppressor gene dysfunction in neuroblastoma.
- To discuss emerging therapeutic strategies targeting TSG-associated vulnerabilities.
- To highlight the role of interconnected signaling networks in neuroblastoma progression and treatment resistance.
Main Methods:
- Literature review of genomic and epigenomic evidence.
- Analysis of molecular mechanisms underlying TSG dysfunction.
- Discussion of current and emerging therapeutic strategies.
Main Results:
- Neuroblastoma frequently involves TSG dysfunction via deletions, copy number alterations, and epigenetic silencing.
- Key affected pathways include Tp53, RB, PTEN/PI3K/AKT, Hippo, and DNA damage response.
- These disruptions drive tumor progression, metastasis, immune evasion, metabolic adaptation, and therapeutic resistance.
Conclusions:
- Understanding TSG network dysfunction is crucial for improving high-risk neuroblastoma outcomes.
- Targeting interconnected oncogenic, epigenetic, metabolic, and immune networks presents promising therapeutic avenues.
- Clinical translation faces challenges including tumor heterogeneity, toxicity, and adaptive resistance.
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