Abstract
Neuroblastoma is an embryonal tumor of childhood with a heterogenous clinical presentation that reflects differences in activation of complex biological signaling pathways. Protein phosphorylation is a key component of cellular signal transduction and plays a critical role in processes that control cancer cell growth and survival. We used shotgun LC/MS to compare phosphorylation between a human MYCN amplified neuroblastoma cell line (NB10), modeling a resistant tumor, and a human neural precursor cell line (NPC), modeling a normal baseline neural crest cell. 2181 unique phosphorylation sites representing 1171 proteins and 2598 phosphopeptides were found. Protein kinases accounted for 6% of the proteome, with a predominance of tyrosine kinases, supporting their prominent role in oncogenic signaling pathways. Highly abundant receptor tyrosine kinase (RTK) phosphopeptides in the NB10 cell line relative to the NPC cell line included RET, insulin-like growth factor 1 receptor/insulin receptor (IGF-1R/IR), and fibroblast growth factor receptor 1 (FGFR1). Multiple phosphorylated peptides from downstream mediators of the PI3K/AKT/mTOR and RAS pathways were also highly abundant in NB10 relative to NPC. Our analysis highlights the importance of RET, IGF-1R/IR and FGFR1 as RTKs in neuroblastoma and suggests a methodology that can be used to identify potential novel biological therapeutic targets. Furthermore, application of this previously unexploited technology in the clinic opens the possibility of providing a new wide-scale molecular signature to assess disease progression and prognosis.
Highlights
Neuroblastoma is an embryonal tumor of the sympathetic nervous system that is remarkable for its heterogeneity, including both its biology and clinical behavior [1]
Phosphoproteomic profiling of neuroblastoma and neural progenitor cells To determine the differences in phosphopeptide abundance in neuroblastoma cells compared with normal neural crestderived cells, we isolated proteins from the NB10 cell line, representing a high-risk MYCN amplified cell line, and from an neural precursor cell line (NPC) line, representing a control human neural crest cell line
In this work we demonstrate that MYCN-amplified neuroblastoma cells contain elevated levels of multiple phosphopeptides from receptor tyrosine kinases capable of activating several downstream signaling pathways
Summary
Neuroblastoma is an embryonal tumor of the sympathetic nervous system that is remarkable for its heterogeneity, including both its biology and clinical behavior [1]. The broad spectrum of neuroblastoma clinical disease encompasses very low-risk infants whose tumors are treated with surgical resection alone and a subset of patients with high-risk factors whose disease treatment involves an intensive multimodal approach including dose-intensive chemotherapy, surgery, stem cell transplant, radiotherapy, and immunotherapy [2]. Despite this aggressive approach to treatment, high-risk neuroblastoma has a 5 year overall survival of only 40% [3]. Gene expression profiling studies have identified a unique 59 gene neuroblastoma tumor signature that is associated with an unfavorable prognosis [10]
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