Metabolic Reprogramming and Extracranial Solid Tumor Evolution in Infants

Abstract

Disease progression after intensive multi modal clinical therapy poses grave concern not only on the quality of life but on the very survival of children presented with neuroblastoma. Acquired modifications of energy metabolism in the tumor cells that defy clinical therapy plays pivotal role in frequent and rapid tumor relapse. We investigated the mechanisms of how these cells adopt metabolic rearrangements with therapy pressure. Our earlier findings showed the constitutive availability of retinal degeneration protein 3 (RD3) in human fetal tissues beyond retina, displayed its functional role in tumor pathogenesis, and unearthed its significance in neuroblastoma clinical outcomes. Herein, with the gene surrogate strategy, the whole genome RNA sequencing in reverse engineered (bed-to-bench) patient derived cell lines showed a patient-independent, RD3-dependent stabilization of metabolic programming. Loss of RD3 altered crucial metabolic pathways and coordinated metabolic mayhem in high-risk stage-4 disease. Evaluating the glycolysis phenotype with seahorse revealed that RD3 loss dependent increase in extracellular acidification rate (EACR) associated with glycolysis, glycolytic capacity and glycolytic reserves in therapy defying progressive disease. Critically, therapeutic delivery of RD3 (custom archived and characterized RD3 peptide candidates) significantly deregulated glycolysis in such progressive disease that lack RD3, recognizing a RD3-dependent regulation of metabolic activity. Our study outcomes clearly portrayed the thus far unrealized significance of therapy pressure driven RD3 loss mediated metabolism deregulation in neuroblastoma. Crucially, these new findings will pave way for the identification of a novel targeted maintenance therapeutic strategy for treatment of this deadly disease.