biostudies-literatureCouto JPEuropean Molecular Biology OrganizationSwiss National Science FoundationEuropean Research CouncilPromedica StiftungH2020 Marie Skłodowska-Curie ActionsKrebsliga SchweizNovartise112559https://www.ebi.ac.uk/biostudies/studies/S-EPMC10308372biostudies-literatureUnknown42(13)Metastatic colonization of distant organs accounts for over 90% of deaths related to solid cancers, yet the molecular determinants of metastasis remain poorly understood. Here, we unveil a mechanism of colonization in the aggressive basal-like subtype of breast cancer that is driven by the NAD⁺ metabolic enzyme nicotinamide N-methyltransferase (NNMT). We demonstrate that NNMT imprints a basal genetic program into cancer cells, enhancing their plasticity. In line, NNMT expression is associated with poor clinical outcomes in patients with breast cancer. Accordingly, ablation of NNMT dramatically suppresses metastasis formation in pre-clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA methThe EMBO journalNicotinamide N-methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer.PMC10308372F‐87701‐41‐01841872694033Schmidt AObradovic MMFrei ALIvanek RMertz KDKoelzer VHVarga ZJehanno CSethi AHamelin BManivannan MGomez-Miragaya JCouto JPVulin MBentires-Alj MCoissieux MMBrautigam KHager CfalseNicotinamide N-methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer.Metastatic colonization of distant organs accounts for over 90% of deaths related to solid cancers, yet the molecular determinants of metastasis remain poorly understood. Here, we unveil a mechanism of colonization in the aggressive basal-like subtype of breast cancer that is driven by the NAD⁺ metabolic enzyme nicotinamide N-methyltransferase (NNMT). We demonstrate that NNMT imprints a basal genetic program into cancer cells, enhancing their plasticity. In line, NNMT expression is associated with poor clinical outcomes in patients with breast cancer. Accordingly, ablation of NNMT dramatically suppresses metastasis formation in pre-clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA meth2023-01-01T00:00:00Z2023 Jul2026-06-01T20:25:44.96Z2026-05-20T03:08:11.455ZS-EPMC103083723725959610.15252/embj.2022112559