NAMPT overexpression induces cancer stemness and defines a novel tumor signature for glioma prognosis

Abstract

Gliomas are the most prevalent primary malignant brain tumors associated with poor prognosis. NAMPT, a rate-limiting enzyme that boosts the nicotinamide adenine dinucleotide (NAD) regeneration in the salvage pathway, is commonly expressed in these tumors. NAD metabolism is required to maintain tissue homeostasis. To maintain metabolism, cancer cells require a stable NAD regeneration circuit. However, high levels of NAD confer resistance to therapy to these tumors, usually treated with Temozolomide (TMZ). We report that NAMPT overexpression in glioma cell lines increases tumorigenic properties controlling stem cell pathways and enriching the cancer-initiating cell (CIC) population. Furthermore, NAMPT expression correlated with high levels of Nanog, CD133 and CIC-like cells in glioblastoma directly extracted from patients. Meta-analysis reveals that NAMPT is also a key factor inducing cancer stem pathways in glioma cells. Furthermore, we report a novel NAMPT-driven signature which stratify prognosis within tumor staging. NAMPT signature also correlates directly with EGFR positive and IDH negative tumors. Finally, NAMPT inhibition increases sensitivity to apoptosis in both NAMPT-expressing cells and tumorspheres. Therefore, NAMPT represents a novel therapeutic target in Glioma progression and relapse.

A statistical framework for assessing pharmacological response and biomarkers using uncertainty estimates

“…It has been clinically tested in melanoma (ClinicalTrials.gov Identifier: NCT00432107), Refractory B-CLL (NCT00435084) and Cutaneous T-cell Lymphoma (NCT00431912), whilst showing anti-proliferative effect in glioblastoma cell lines 26 . Therapeutic potential when combining with other drugs used to treat gliomas 27,28 has been suggested, while we additionally and concordantly identify EGFR amplification as a biomarker ( Figure 4F ).…”

NAMPT, GRN, and SERPINE1 signature as predictor of disease progression and survival in gliomas

“…Our results are consistent with their findings suggesting increased NAMPT levels as the worst prognosticator in GBM samples. NAMPT has been suggested to act as a dedifferentiation inducer gene controlling energy core axis for glioma cancer stem like cells maintenance . Liu et al reported that elevated levels of NAMPT in the serum of small cell lung cancer (SCLC) patients were associated with brain metastasis and CCL2 was involved in transendothelial migration of tumor cells across the BBB.…”

“…Lucena‐Cacace et al suggested that high expression of NAMPT and SERPINE1 correlated with IDH1 wild type GBM tumors leading to the worst prognosis. They also proposed that NAMPT overexpression in glioma cell lines increases the tumorogenic properties . IDH wild type LGG vessels are molecularly distinct from the IDH1 mutated, therefore indicative of vascular remodeling and angiogenesis .…”

“…NAMPT has been suggested to act as a dedifferentiation inducer gene controlling energy core axis for glioma cancer stem like cells maintenance. 16,17 Liu et al 17 reported that elevated levels of NAMPT in the serum of small cell lung cancer (SCLC) patients were associated with brain metastasis and CCL2 was involved in transendothelial migration of tumor cells across the BBB. Our results also indicated upregulation of CCL2 and association with adverse prognosis in LGG and GBM.…”

“…They also proposed that NAMPT overexpression in glioma cell lines increases the tumorogenic properties. 16 IDH wild type LGG vessels are molecularly distinct from the IDH1 mutated, therefore indicative of vascular remodeling and angiogenesis. 35 We believe more studies with large number of samples of multiple ethnicities are warranted before establishing NAMPT and SERPINE1 overexpression as a surrogate biomarker for adverse prognosis within IDH1 wild type LGG subgroup.…”