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Negr1-Derived Peptides Trigger ALK Degradation and Halt Neuroblastoma Progression In Vitro and In Vivo
Francesca Pischedda1, Alessia Ghirelli1, Vasvi Tripathi1
1Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123 Trento, Italy.
Abstract:
Neuroblastoma is among the most common childhood cancers. Neuroblastoma in advanced stages is one of the most intractable pediatric cancers, notwithstanding the recent therapeutic advances. ALK mutations are among the leading cause of hereditary neuroblastoma and account for more than 14% of the somatically acquired alterations. ALK kinase activity is currently one of the main targets for pharmacological strategies. However, evidence from ALK fusion-positive lung cancer studies has shown that resistance to ALK inhibition arises during the therapy, causing a relapse within several years. IgLONs are membrane-bound proteins involved in cell-to-cell adhesion. The expression of the IgLON family results altered in different cancers. We found that the IgLON member Negr1 is downregulated in neuroblastoma. The ectopic overexpression of Negr1 impairs neuroblastoma growth in vitro and in vivo. Negr1 exists as a GPI-anchored membrane-bound protein and as a soluble protein released upon metalloprotease cleavage. We generated and characterized a panel of Negr1-derived peptides. The treatment with Negr1 protein and derived peptides induce ALK downregulation and halt neuroblastoma progression in vitro and in vivo.
Insights
Negr1 protein and peptides can halt neuroblastoma progression by downregulating ALK. This discovery offers a new therapeutic strategy for this intractable childhood cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neuroblastoma is a prevalent and challenging pediatric cancer, with advanced stages often resistant to current treatments.
- Anaplastic Lymphoma Kinase (ALK) mutations are key drivers in hereditary and sporadic neuroblastoma, making ALK a primary therapeutic target.
- Resistance to ALK inhibitors can lead to relapse, necessitating novel therapeutic approaches.
Purpose of the Study:
- To investigate the role of Immunoglobulin-like domain containing, cell adhesion molecule 1 (IgLON1), specifically Negr1, in neuroblastoma.
- To evaluate the therapeutic potential of Negr1 protein and its derived peptides in preclinical neuroblastoma models.
Main Methods:
- Analysis of Negr1 expression in neuroblastoma samples.
- In vitro and in vivo experiments involving ectopic Negr1 overexpression.
- Characterization of Negr1 protein and derived peptides.
- Assessment of ALK downregulation and neuroblastoma progression following Negr1-based treatment.
Main Results:
- Negr1 expression is downregulated in neuroblastoma.
- Ectopic Negr1 expression inhibits neuroblastoma cell growth both in vitro and in vivo.
- Treatment with Negr1 protein and peptides effectively downregulates ALK and halts tumor progression.
- Negr1 functions as both a membrane-bound and soluble protein, with peptides demonstrating therapeutic efficacy.
Conclusions:
- Negr1 represents a novel tumor suppressor in neuroblastoma.
- Negr1 protein and its derived peptides show significant therapeutic promise for treating neuroblastoma by targeting ALK.
- This study introduces a new therapeutic avenue for managing advanced neuroblastoma and overcoming resistance mechanisms.
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