Molecular symphony: unveiling the role of Nicotinamide Phosphoribosyltransferase (NAMPT) in the bad harmony of cancer landscape

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor involved in regulating key processes such as energy metabolism and cell survival. The intracellular form of nicotinamide phosphoribosyltransferase (iNAMPT) participates in NAD+ biosynthesis. Given the high turnover of NAD+ in cancer cells and the overexpression of NAMPT in different cancers, several inhibitors have been developed. However, clinical trials did not demonstrate a sufficient benefit/risk yet. In this context, one of the aim of this Ph.D thesis was to use proteolysis-targeting chimeras (PROTACs) targeting NAMPT to overcome some limitations associated with traditional inhibitors. To date, NAMPT even exists as an extracellular form (eNAMPT) which has been shown to be released by several cancer types and exert paracrine and autocrine functions. In cancer, it has been demonstrated that most cancer patients have elevated levels of eNAMPT in serum and plasma compared to healthy individuals, and these elevated levels correlate with poor prognosis. In addition, eNAMPT, as cytokine, has been implicated in various tumour-associated activities. Although eNAMPT is reported to be a pro-angiogenic molecule for endothelial cells, the link between eNAMPT and tumour angiogenesis, critical for tumour progression and metastasis, is wanting. Moreover, the blood vessels bed is not solely composed of endothelial cells. Pericytes, mural cells that surround endothelial cells lining the vessels, play a crucial role in regulating blood flow, vessel stability, and the formation of new blood vessels. Pericyte density around the tumour vessel wall is a key factor in determining cancer progression. Given the absence in literature connecting eNAMPT to pericytes, during my Ph.D thesis I mainly investigated the involvement of eNAMPT in the pathophysiology of pericytes, exploring whether this cytokine is essential for their activities and if it impacts tumour angiogenesis in eNAMPT-enriched tumours.