ADO/hypotaurine: a novel metabolic pathway contributing to glioblastoma development

Abstract

Abstract Significant advance has been made towards understanding glioblastoma metabolism through global metabolomic profiling. However, hitherto little is known about the role by which altered metabolism plays in driving the aggressive glioma phenotype. We have previously identified hypotaurine as one of the top-ranked metabolites for differentiating low- and high-grade tumors, and that there is also a strong association between the levels of intratumoral hypotaurine and expression of its biosynthetic enzyme, cysteamine (2-aminoethanethiol) dioxygenase (ADO). Using transcription profiling, we further uncovered that the ADO/hypotaurine axis targets CCL20 secretion through activating the NF-κB pathway to drive the self-renewal and maintenance of glioma ‘cancer stem cells’ or glioma cancer stem-like cells. Conversely, abrogating the ADO/hypotaurine axis using CRISPR/Cas9-mediated gene editing limited glioblastoma cell proliferation and self-renewal in vitro and tumor growth in vivo in an orthotopical mouse model, indicating that this metabolic pathway is a potential key therapeutic target. Collectively, our results unveil a targetable metabolic pathway, which contributes to the growth and progression of aggressive high-grade gliomas, as well as a novel predictive marker for glioblastoma diagnosis and therapy.