Multi-omic analyses of the MYCN network unveil new potential vulnerabilities in childhood neuroblastoma

Neuroblastoma is the first neurogenic-extracranial solid cancer occurring in infancy and childhood. The genetic aberration most commonly associated with a poor prognosis is MYCN gene’s amplification. We hypothesize that effective anti-MYC therapeutics can be developed by understanding the regulation and function of N-MYC in neuroblastoma. Since N-MYC is an intrinsically disordered protein, it is still challenging to target this transcription factor, however, the model is shifting significantly after discovering novel therapeutic targets that impact MYC-driven tumorigenesis. The following work explores how MYCN expression affects the induction and maintenance of neuroblastoma. By using different multi-omic approaches and many promising innovative techniques, we were able to identify and characterize new potential vulnerabilities of this pathology, which may work in concert with N-MYC for the instruction of a high-risk neuroblastoma phenotype. My studies’ first objective was to investigate whether and how N-MYC can regulate transcription of lncRNAs by comparing transcriptional profiles between non-amplified and MYCN-amplified neuroblastoma cells. Here, we singled out lncNB1, which is selectively higher expressed in high MYCN cells only and it is also firmly and almost uniquely transcribed in neuroblastoma among all types of cancers. Our data showed that N-MYC directly activates transcription of lncNB1, instructing a complex network of molecular interactions, ultimately resulting in increased N-MYC protein stability, reinforcing the N-MYC oncogenetic program. The second objective was to assess how high N-MYC expression may cooperate to establish a dynamic regulatory axis with the E2F3 transcription factor, impacting the development of the high-risk cancer phenotype. Taken together, our unbias screenings uncovered potential candidates that help to fill the knowledge gap in understanding what is the impact of N-MYC in childhood neuroblastoma, providing new opportunities for the development of specific treatments able to target the function of MYC oncoproteins in a context of MYCN gene amplification.