Stromal nicotinamide N-methyltransferase orchestrates the crosstalk between fibroblasts and tumour cells in oral squamous cell carcinoma: evidence from patient-derived assembled organoids
Stromal nicotinamide N-methyltransferase orchestrates the crosstalk between fibroblasts and tumour cells in oral squamous cell carcinoma: evidence from patient-derived assembled organoids
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DOI：
10.1038/s41388-023-02642-5
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发表时间：
2023-02
期刊：
影响因子：
8
通讯作者：
Hui-Qi Zhao;Rui Li;Yang Chen;X. Yang;Z. Shang
中科院分区：
文献类型：
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作者：
Hui-Qi Zhao;Rui Li;Yang Chen;X. Yang;Z. Shang
据报道，烟酰胺N-甲基转移酶（NNMT）与癌细胞中的甲基化重编程有关。然而，NNMT在肿瘤微环境（TME）中的作用仍然难以捉摸。在此，我们发现NNMT在口腔鳞状细胞癌（OSCC）间质中的表达升高。使用成纤维细胞附着的类器官（FAOs）模型，我们证实了基质NNMT表达有助于组装肿瘤类器官的产生。在与共同植入的OSCC细胞和癌症相关的成纤维细胞（CAFs）的肿瘤再生试验中，当NNMT在CAFs中沉默时，肿瘤起始活性降低。相比之下，在癌旁成纤维细胞（PF）中过度表达NNMT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NNMT可以调节FAOs和异种移植物中的I型胶原沉积。进一步的研究证实，基质NNMT加重的致癌活性通过用成纤维细胞中的胶原合成抑制剂（例如氯沙坦、曲尼司特和常山酮）或癌细胞中的粘着斑激酶（FAK）信号抑制剂（即defactinib）治疗而减弱。从机制上讲，NNMT的过表达减少了编码赖氨酰氧化酶（LOX）的基因启动子处H3 K27 me 3的富集，LOX是调节胶原I交联的关键酶。总体而言，我们认为NNMT-LOX-FAK级联有助于OSCC发展过程中癌细胞和成纤维细胞之间的串扰，并且NNMT为中心的细胞外基质重塑是OSCC患者的新治疗靶点。
NicotinamideN-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.