NAMPT as a Dedifferentiation-Inducer Gene: NAD+ as Core Axis for Glioma Cancer Stem-Like Cells Maintenance

Abstract

Glioma Cancer Stem-Like Cells (GSCs) are a small subset of CD133⁺ cells with self-renewal properties and capable of initiating new tumors contributing to Glioma progression, maintenance, hierarchy, and complexity. GSCs are highly resistant to chemo and radiotherapy. These cells are believed to be responsible for tumor relapses and patients' fatal outcome after developing a recurrent Glioblastoma (GBM) or High Grade Glioma (HGG). GSCs are cells under replicative stress with high demands on NAD⁺ supply to repair DNA, maintain self-renewal capacity and to induce tumor plasticity. NAD⁺ feeds Poly-ADP polymerases (PARP) and NAD⁺-dependent deacetylases (SIRTUINS) contributing to GSC phenotype. This energetic core axis is mainly controlled by the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT), an important oncogene contributing to tumor dedifferentiation. Targeting GSCs depicts a new frontier in Glioma therapy; hence NAMPT could represent a key regulator for GSCs maintenance. Its inhibition may attenuate GSCs properties by decreasing NAD⁺ supply, consequently contributing to a better outcome together with current therapies for Glioma control.

Keywords: GBM; GSCs; Glioma; NAD; NAMPT; PARP; SIRT; TMZ.

Figure 1

Glioma cell(s) of origin and NAD⁺ relative consumption. The size of the font indicates the relative NAD⁺ consumption.

Figure 2

NAMPT/Nicotinamide adenine dinucleotide metabolism. Four major synthesis precursors (Exogenous NA, exogenous NAM, NR, and Tryptophan, dark gray) are divided between two major pathways: de novo pathway (light green), and salvage pathway (light purple).

Figure 3

Schematic representation of GSCs' replication stress and NAD⁺-dependent DNA repair mechanisms. TMZ induces DNA damage in chromosomal DNA in GSCs. PARPs-based DNA repair defines chemosensitivity. PARPs efficacy relies on NAD⁺ levels mainly controlled by NAMPT. NAMPT dually governs NAD⁺ production and maintain CSC-like properties in GSCs.

Figure 4

Single-cell transcriptomic analysis of GSE84465 for NAMPT expression in GBM. (A) 3,589 cells in a cohort of 4 patients are categorized by cell identity (Normal vs. Tumoral) and clusters based on differences on transcriptomic profiles based on heterogenic distribution on dimensions 1 and 2 of t-distributed stochastic neighbor embedding (tSNE). Three tumors clusters are highlighted on dashed circles. Cluster number 10 is transcriptionally allotted to GSC-cells subset. (B) Single-cell transcriptomic distribution for GSC-related markers expression in correlation to NAMPT expression. (C) NAMPT expression analysis classified by different cell identities from normal and tumor tissue. (D) Supervised hierarchical clustering of NAMPT, NNMT, DNMT1, DNMT3A, DNMT3B, and DNMT3L mRNA expression in tumor cell clusters (9, 10, and 11).