INVESTIGATING eNAMPT ROLE IN ACQUISITION OF EPITHELIAL TO MESENCHYMAL TRANSITION-LIKE FEATURES IN MULTIPLE MYELOMA

Background and preliminary data:

Multiple myeloma (MM) is characterized by a clonal expansion of malignant plasma cells in the bone marrow (BM) with a continuous spread of tumour cells in and out of BM. A continuous interaction between BM stromal cells (BMSCs) and MM cells supports proliferation, survival, migration, and drug resistance of tumor cells. Indeed, BMSCs by both cytokines production and cell-cell interactions, control the ability of MM cells to enter into bloodstream, leading to homing or extravasation of clonal cells into distant tissues, which in turn results in new BM niches formation.

The epithelial-to-mesenchymal transition (EMT) is a biological phenomenon by which epithelial cells can switch into a mesenchymal phenotype through the disruption of cell-cell adhesion and cellular polarity, remodeling of cytoskeleton and changing cell-matrix adhesion. Overall, these events lead to improved migratory and invasive properties of affected cells. Remarkably, EMT occurs physiologically during normal embryonic development and tissue regeneration but, in cancer cell, it has been associated with tumor aggressiveness features including invasion, metastasis, stemness and drug-resistance. EMT is commonly observed in solid tumors but it has been recently described also in MM. In such a context, studies have shown that BM niches-associated hypoxia produces MM cells egress and dissemination through acquisition of EMT-like features which in turn, by increasing CXCR4 expression, produces extra-medullary disease (EMD) development.

Alterations in cell metabolism have emerged as one of the hallmarks of cancer that could be possibly targeted by novel therapeutic approaches. Among these alterations, biosynthesis of nicotinamide adenine dinucleotide (NAD+) is emerging as novel therapeutic target in tumours. Nicotinamide phosphorybosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ production from nicotinamide (NAM) in mammalian cells, is frequently up-regulated in cancers, including MM, and its relevance as potential therapeutic target has been widely explored by our group. However, beside its intracellular activity as key metabolic enzyme, NAMPT is also present in the extracellular milieu where it exerts cytokine/adipokine-like actions as eNAMPT. Although mechanisms underlying eNAMPT secretion still remain to be elucidated, it is commonly accepted that there is positive correlation between eNAMPT secretion and intracellular NAMPT levels. Recent evidences show that eNAMPT plasma levels are significantly higher in cancer patients in comparison with healthy donors in several hematologic and solid neoplasms. In this context, eNAMPT was found to exert pro-tumorigenic effects such as promoting cancer cell proliferation and colonies formation, conferring resistance to apoptosis and shaping of tumour microenviroment, by promoting neo-angiogenesis and affecting immune response.

The Investigators recently demonstrated the pivotal role played by eNAMPT in the acquisition of EMT in human breast cancer cells. In detail, NAMPT overexpression promotes acquisition of fibroblast-like morphology of cancer cells by reducing E-cadherin expression in association with N-cadherin, Vimentin and ZEB1 upregulation. Importantly, NAMPT-induced EMT is not associated with NAMPT enzymatic activity and neither with its product levels nicotinamide mononucleotide (NMN). On the contrary, EMT seems to be mediated by eNAMPT through its ability to activate TGFβ signaling pathway via increased TGFβ1 production.