Nicotinamide N-methyltransferase（NNMT）被报道与癌细胞DNA甲基化重编程相相关联。然而，NNMT在肿瘤微环境（TME）中的作用尚不清楚。在这里，我们发现NNMT表达在口腔鳞状细胞癌（OSCC）的基质中升高。使用成纤维细胞附着的器官样（FAO）模型，我们证实基质NNMT表达有助于生成组装的肿瘤器官样。在与癌相关成纤维细胞（CAF）嵌合的OSCC细胞的肿瘤再生实验中，当CAF中的NNMT被沉默时，肿瘤启动活性减少。相反，NNMT在癌旁成纤维细胞中过表达加速了共接种实验中的肿瘤生长。值得注意的是，成纤维细胞特异性的NNMT可以调节FAO和异种移植物中的I型胶原沉积。进一步的研究证实，通过抑制细胞外基质合成（例如，洛卡新，曲莫司汀和衮苷）或癌细胞的焦点粘附激酶（FAK）信号（即defactinib）的抑制剂可以减轻基质NNMT加重的致癌活性。机械上，NNMT的过表达减少了量编码赖氨酸氧化酶（LOX）的基因启动子处的H3K27me3富集，LOX是调节I型胶原交联的关键酶。总的来说，我们认为NNMT-LOX-FAK级联作用有助于癌细胞和成纤维细胞在OSCC发展期间的相互交流，并且基于NNMT的细胞外基质重塑是OSCC患者的新型治疗靶点。© 2023年。作者（被授权）授予Springer Nature Limited独家使用许可。

Nicotinamide N-methyltransferase (NNMT) has been reported to be linked to methylation reprogramming in cancer cells. However, the role of NNMT in the tumour microenvironment (TME) remains elusive. Here, we found that the expression of NNMT was elevated in the stroma of oral squamous cell carcinoma (OSCC). Using a fibroblast-attached organoids (FAOs) model, we confirmed that stromal NNMT expression contributed to the generation of assembled tumour organoids. In a tumour regeneration assay with co-implanted OSCC cells and cancer-associated fibroblasts (CAFs), the tumour-initiating activity was reduced when NNMT was silenced in CAFs. In contrast, overexpression of NNMT in paracancerous fibroblasts (PFs) accelerated tumour growth in co-inoculation experiments. Notably, fibroblast-specific NNMT can regulate type I collagen deposition in both FAOs and xenografts. Further investigations confirmed that the stromal NNMT-aggravated oncogenic activities were attenuated by treatment with inhibitors of either collagen synthesis (e.g. losartan, tranilast, and halofuginone) in fibroblasts, or the focal adhesion kinase (FAK) signal (i.e. defactinib) in cancer cells. Mechanistically, overexpression of NNMT reduced the enrichment of H3K27me3 at the promoter of the gene encoding lysyl oxidase (LOX), a key enzyme that regulates the cross-linking of collagen I. Overall, we propose that the NNMT-LOX-FAK cascade contributes to the crosstalk between cancer cells and fibroblasts during OSCC development, and that NNMT-centric extracellular matrix remodelling is a novel therapeutic target for patients with OSCC.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.