Mak Tsz Kin, Li Kuan, Zhao Zidan, Wang Kexin, Zeng Leli, He Qilang, Lu Weiqun, Chen Wei, He Yulong, Li Jia, Zhang Changhua
Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China; Department of Gastrointestinal Tumor Surgery, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510095, China.
Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
Cancer Lett. 2024 Dec 24;611:217422. doi: 10.1016/j.canlet.2024.217422.
Cancer associated fibroblasts (CAFs) are the predominant stromal cells in the tumor microenvironment of gastric cancer (GC), interacting with both immune and tumor cells to drive cancer progression. However, the precise link between these interactions and their potential as therapeutic targets remains poorly understood. In this study, we identified for the first time that nicotinamide N-methyltransferase (NNMT) derived from CAFs promoted M2 macrophage polarization, which, in turn, facilitated the proliferation and migration of GC cells. Additionally, we discovered that NNMT expression in CAFs was regulated by the Fat mass and obesity related protein (FTO) via m6A demethylation. Both NNMT and FTO were highly expressed in tumor tissues and CAFs, with a positive correlation between FTO and NNMT levels in clinical samples. Mechanistically, FTO bound to NNMT mRNA, reducing m6A modification and enhancing NNMT expression. Knockdown of either NNMT or FTO in CAFs effectively inhibited M2 macrophage polarization and suppressed GC progression. These findings were validated in patient-derived organoid models and nude mouse models of GC. Collectively, our data revealed that FTO promoted M2 macrophage polarization by regulating the m6A demethylation of NNMT in CAFs, thereby driving GC progression. This identified a potential novel target for GC diagnosis and therapy.
癌症相关成纤维细胞（CAFs）是胃癌（GC）肿瘤微环境中的主要基质细胞，与免疫细胞和肿瘤细胞相互作用以推动癌症进展。然而，这些相互作用与其作为治疗靶点的潜力之间的确切联系仍知之甚少。在本研究中，我们首次发现源自CAFs的烟酰胺N-甲基转移酶（NNMT）促进M2巨噬细胞极化，进而促进GC细胞的增殖和迁移。此外，我们发现CAFs中NNMT的表达受脂肪量和肥胖相关蛋白（FTO）通过m6A去甲基化的调节。NNMT和FTO在肿瘤组织和CAFs中均高表达，临床样本中FTO和NNMT水平呈正相关。机制上，FTO与NNMT mRNA结合，减少m6A修饰并增强NNMT表达。在CAFs中敲低NNMT或FTO可有效抑制M2巨噬细胞极化并抑制GC进展。这些发现已在源自患者的类器官模型和GC裸鼠模型中得到验证。总体而言，我们的数据表明FTO通过调节CAFs中NNMT的m6A去甲基化促进M2巨噬细胞极化，从而推动GC进展。这确定了一个潜在的GC诊断和治疗新靶点。
