Abstract
c-Myc dysregulation is hypothesized to account for the ‘stemness’ – self-renewal and pluripotency – shared between embryonic stem cells (ESCs) and adult aggressive tumours. High-risk neuroblastoma (HR-NB) is the most frequent, aggressive, extracranial solid tumour in childhood. Using HR-NB as a platform, we performed a network analysis of transcriptome data and presented a c-Myc subnetwork enriched for genes previously reported as ESC-like cancer signatures. A subsequent drug-gene interaction analysis identified a pharmacogenomic agent that preferentially interacted with this HR-NB-specific, ESC-like signature. This agent, Roniciclib (BAY 1000394), inhibited neuroblastoma cell growth and induced apoptosis in vitro. It also repressed the expression of the oncogene c-Myc and the neural ESC marker CDK2 in vitro, which was accompanied by altered expression of the c-Myc-targeted cell cycle regulators CCND1, CDKN1A and CDKN2D in a time-dependent manner. Further investigation into this HR-NB-specific ESC-like signature in 295 and 243 independent patients revealed and validated the general prognostic index of CDK2 and CDKN3 compared with CDKN2D and CDKN1B. These findings highlight the very potent therapeutic benefits of Roniciclib in HR-NB through the targeting of c-Myc-regulated, ESC-like tumorigenesis. This work provides a hypothesis-driven systems computational model that facilitates the translation of genomic and transcriptomic signatures to molecular mechanisms underlying high-risk tumours.
Highlights
Evidence from heterogeneous primary tumours suggests the common presence of a rare cellular subpopulation, termed tumour-initiating cells, that exhibits self-renewal and chemo-resistance properties reminiscent of those of normal stem cells[1,2,3,4]
This study computationally extracted the importance of c-Myc from transcriptomic confluence and genetic interruptions in both HR-NB and the embryonic stem cells (ESCs)-like cancer signatures
Coupled with in vitro evidence, this study further extended the emerging inhibitory effects of cyclin-dependent kinase (CDK) inhibitors in HR-NB into previously uncharacterized impacts on tumour apoptosis
Summary
Evidence from heterogeneous primary tumours suggests the common presence of a rare cellular subpopulation, termed tumour-initiating cells, that exhibits self-renewal and chemo-resistance properties reminiscent of those of normal stem cells[1,2,3,4]. The phenotypes of a specific type of normal stem cell, embryonic stem cells (ESCs), have frequently been associated with the molecular and functional characteristics of several aggressive and treatment resistant tumours[5, 6]. How systematic computational approaches can help depict the ESC-like, cancer-activated gene signatures that underpin the translational regulatory network shared by heterogeneous aggressive tumours remains unclear. Patients with high-risk (HR) NB exhibit greater than 60% mortality and recurrence rates[7] This tumour cell population is resistant to chemoand radiotherapy and often possesses the functional and molecular characteristics of normal stem cells. Deciphering the role of c-Myc in this high-risk state as well as the associated functional and molecular characteristics of ESCs in HR-NB, will offer a comprehensive understanding of malignant translational regulation. “Hub” proteins are highly connected in complex networks and tend to be more essential than non-hub proteins[21], whereas “bottleneck” proteins retain the shortest paths (analogous to major bridges and tunnels on a highway map) and correlate with gene essentiality and expression dynamics[24, 25]
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