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G-CSF/NAMPT signaling drives neutrophil dysfunction and enhances bacterial infection susceptibility in cancer patients

ABSTRACT: Despite advancements in cancer therapies, bacterial complications remain a major challenge, delaying treatment and worsening outcomes. While immunosuppressive therapies and prolonged hospitalizations contribute, they do not fully explain the elevated infection risk in cancer patients. Here we show that tumors producing high levels of granulocyte colony-stimulating factor (G-CSF) promote the persistence of Gram-negative pathogens in head and neck squamous cell carcinoma. We identify tumor-driven activation of the nicotinamide phosphoribosyltransferase (NAMPT)- nicotinamide adenine dinucleotide (NAD) signaling axis in neutrophil progenitors, resulting in impaired phagocytosis and neutrophil extracellular traps formation, accelerated neutrophil aging, and buildup of tissue-damaging neutrophil subsets. This disrupts lung tissue integrity and facilitates bacterial persistence. Importantly, targeting the G-CSF-NAMPT pathway prevents the generation of dysfunctional neutrophils and improves bacterial clearance in vivo. Our findings reveal tumor-induced, NAMPT-dependent neutrophil reprogramming as a central driver of compromised antimicrobial defenses in cancer. Therapeutic strategies aimed at modulating G-CSF-NAMPT signaling could enhance infection control and survival for cancer patients

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Hannah Voss

LAB HEAD: Olga Shevchuk

PROVIDER: PXD069569 | Pride | 2025-10-17

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	2025_July_HV_AG_Jablonska_Lung_Proteome_Revision.sne	Other
	M4_1_300ng_S1-A1_1_4953.d.zip	Other
	M4_2_300ng_S1-A2_1_4955.d.zip	Other
	M4_3_300ng_S1-A3_1_4957.d.zip	Other
	M4_4_300ng_S1-A4_1_4959.d.zip	Other

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Project 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.

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G-CSF/NAMPT signaling drives neutrophil dysfunction and enhances bacterial infection susceptibility in cancer patients

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