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 methylation at the promoters of PR/SET Domain-5 (PRDM5) and extracellular matrix-related genes. PRDM5 emerged in this study as a pro-metastatic gene acting via induction of cancer-cell intrinsic transcription of collagens. Depletion of PRDM5 in tumor cells decreases COL1A1 deposition and impairs metastatic colonization of the lungs. These findings reveal a critical activity of the NNMT-PRDM5-COL1A1 axis for cancer cell plasticity and metastasis in basal-like breast cancer.

中文翻译：

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烟酰胺 N-甲基转移酶维持促进乳腺癌转移定植的核心表观遗传程序

实体癌相关死亡的 90% 以上是由于远处器官的转移定植所致，但人们对转移的分子决定因素仍知之甚少。^{在这里，我们揭示了一种由 NAD +}驱动的侵袭性基底样乳腺癌亚型的定植机制代谢酶烟酰胺 N-甲基转移酶 (NNMT)。我们证明 NNMT 将基础遗传程序印入癌细胞，从而增强其可塑性。与此一致的是，NNMT 表达与乳腺癌患者不良的临床结果相关。因此，在临床前小鼠模型中，NNMT 的消融可显着抑制转移形成。从机制上讲，NNMT 耗尽会导致甲基溢出，从而增加 PR/SET Domain-5 (PRDM5) 和细胞外基质相关基因启动子处的组蛋白 H3K9 三甲基化 (H3K9me3) 和 DNA 甲基化。PRDM5 在这项研究中作为一种促转移基因出现，通过诱导癌细胞内在胶原蛋白转录发挥作用。肿瘤细胞中 PRDM5 的耗竭会减少 COL1A1 沉积并损害肺部的转移定植。