Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology

Abstract

Background Neuroblastoma is a devastating disease accounting for 15% of all childhood cancer deaths. Yet, our understanding of key molecular drivers such as receptor tyrosine kinases (RTKs) in this pathology remains poorly clarified. Here, we provide a systematic analysis of the RTK superfamily in the context of neuroblastoma pathogenesis. Methods Statistical correlations for all RTK family members’ expression to neuroblastoma patient survival across 10 independent patient cohorts were annotated, synthesized, and ranked using the R2: Genomics Analysis and Visualization Platform. Gene expression of selected members across different cancer cell lines was further analyzed in the Cancer Cell Line Encyclopedia, part of the Cancer Dependency Map portal (depmap portal (http://depmap.org)). Finally, we provide a detailed literature review for highly ranked candidates. Results Our analysis defined two subsets of RTKs showing robust associations with either better or worse survival, constituting potential novel players in neuroblastoma pathophysiology, diagnosis, and therapy. We review the available literature regarding the oncogenic functions of these RTKs, their roles in neuroblastoma pathophysiology, and potential utility as therapeutic targets. Conclusions Our systematic analysis and review of the RTK superfamily in neuroblastoma pathogenesis provides a new resource to guide the research community towards focused efforts investigating signaling pathways that contribute to neuroblastoma tumor establishment, growth, and/or aggressiveness and targeting these druggable molecules in novel therapeutic strategies.

Phosphorylation of MYCN and MAX by PAK family kinases is a novel tumor-suppressor mechanism in neuroblastoma with potential therapeutic implications

“…With this in mind, we searched and annotated the potential correlation of the PAK kinase family members to neuroblastoma patient survival probability. In this sense, we annotated the significant Bonferroni-adjusted p-values for all the expression-to-survival correlations (either positive -associated to better outcomes- or negative -associated to reduced survival-) for all 6 members of the PAK family across 11 neuroblastoma patient cohorts (Figure 4A), as previously described 40 . From this analysis, we could observe that PAK2 did not show a significant association with patient survival, suggesting a minor role in neuroblastoma (Figure 4B, left panel).…”

Systems biology network reveals the correlation between COX-2 expression and Ch 7q copy number alterations in Ch 11q-deleted pediatric neuroblastoma tumors

“…Besides the HBS connecting Ch 7q and Ch 11q, there are some that may alone influence COX-inflammation-NB triangle. The HGF/MET complex has been reported to signal migration and/or differentiation of neural crest cell-derived structures [ 33 ], via overexpression, amplification, aberrant splicing, or mutations, associated with many cancer types [ 34 , 35 ]. The HGF/MET complex can also influence COX-2 expression in glioma cells where complex signaling promotes PGE2 release, up-regulating COX-2 expression [ 36 ].…”

Emerging Role and Mechanism of circRNAs in Pediatric Malignant Solid Tumors

“…It is the third most common tumor in children after leukemia and brain tumors ( Zafar et al, 2021 ). Thirty percent of NB tumors occur in the adrenal medulla, about 60% in the abdominal paravertebral ganglia, and the rest in the sympathetic ganglia of the chest, head, neck, and pelvis ( Rozen and Shohet, 2021 ). Currently, many new targeted therapies and immunotherapies have emerged in addition to conventional radiotherapy for NB ( Blavier et al, 2020 ; Bhoopathi et al, 2021 ; Stainczyk and Westermann, 2021 ).…”