PXD063060

PXD063060 is an original dataset announced via ProteomeXchange.

Title	NAMPT and NNMT released via extracellular vesicles and as soluble mediators are distinguished traits of BRAF inhibitor resistance of melanoma cells impacting on the tumor microenvironment
Description	Drugs targeting mutant oncogenes are effective, even though resistance rapidly develops. This complex picture includes acquired intrinsic tumor and tumor microenvironmental -mediated mechanisms. Here we showed that melanoma cells resistant to BRAF inhibitors (BRAFi) overexpressed the rate limiting enzymes involved in nicotinamide (NAM) metabolism nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide N-methyltransferase (NNMT). Importantly, NAMPT and NNMT are released by these cells, both in the free-form or loaded in extracellular vesicles (EVs). NAMPT is emerging as mediator of BRAFi resistance in melanoma, but to date mainly associated with its role as main NAD-biosynthetic enzyme. It had been previously identified as soluble factor, but never in EVs released from melanoma cells, which highlights an impact on the tumor microenvironment (TME). NNMT was revealed increased in melanoma compared to benign nevi, however we showed for the first time its overexpression in resistant cells at intracellular and extracellular levels (present in secretome and in EVs). NNMT increased in BRAF-mutated patients linking its expression with the BRAF oncogenic signaling and correlates positively with pro-inflammatory signaling, immune cell migration and chemokine-mediated signaling pathways opening to a future deeper exploration of its functional role. Lastly, we proposed a tetrameric NNMT:TLR4 binding model offering a plausible structural and mechanistic basis for their association. Overall, the identification of NAMPT and, surprisingly also NNMT, included in EVs and abundantly released from resistant melanoma cells supports the impact of these moonlighting proteins involved in nicotinamide metabolism as mediators of BRAF/MEK inhibitors resistance with tumor intrinsic and potentially tumor microenvironment-mediated mechanisms. Interfering with nicotinamide metabolism could be a valid strategy to counteract drug resistance acting on the multifactorial tumor-host interactions.
HostingRepository	PRIDE
AnnounceDate	2025-07-28
AnnouncementXML	Submission_2025-07-27_16:40:39.975.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD063060
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Romina Belli
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-17 02:22:20	ID requested
⏵ 1	2025-07-27 16:40:40	announced

10.6019/PXD063060;

Ghezzi B, Fiorilla I, Carreira Á, Recco F, Sorci L, Avalle L, Ponzano A, Mazzola F, Todesco AM, Tommasi N, Gasparrini M, D'Agostino VG, Mignone F, Provenzani A, Audrito V, NAMPT and NNMT released via extracellular vesicles and as soluble mediators are distinguished traits of BRAF inhibitor resistance of melanoma cells impacting on the tumor microenvironment. Cell Commun Signal, 23(1):348(2025) [pubmed]

10.1186/s12964-025-02361-2;

submitter keyword: NAMPT

NNMT

metastatic melanoma

resistance

extracellular vesicles

secretome

signaling

tumor microenvironment

Alessandro Provenzani
contact affiliation	Laboratory of Genomic Screening, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
contact email	alessandro.provenzani@unitn.it
lab head
Romina Belli
contact affiliation	University of Trento
contact email	romina.belli@unitn.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD063060
     1. Label: PRIDE project
     2. Name: NAMPT and NNMT released via extracellular vesicles and as soluble mediators are distinguished traits of BRAF inhibitor resistance of melanoma cells impacting on the tumor microenvironment