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ZDHHC13 Modulates Tumor Microenvironment Interactions to Suppress Melanoma Metastasis [scRNA-Seq]

ABSTRACT: This dataset supports a study investigating the role of ZDHHC13 in melanoma development. Using bulk RNA sequencing and 10x Genomics single-cell RNA sequencing, we analyzed how ZDHHC13 influences tumor progression and the tumor microenvironment. These data provide insights into the transcriptomic changes associated with ZDHHC13 activity in melanoma and serve as a resource for understanding gene expression dynamics in both tumor cells and surrounding immune components.

ORGANISM(S): Mus musculus

PROVIDER: GSE302433 | GEO | 2025/09/23

REPOSITORIES: GEO

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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.

Dataset Information

ZDHHC13 Modulates Tumor Microenvironment Interactions to Suppress Melanoma Metastasis [scRNA-Seq]

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