Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multi-plex data from patient tissue, three-dimensional co-culturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. NetG1+ cancer-associated fibroblasts (CAFs) supported PDAC survival, through a NetG1 mediated effect on glutamate/glutamine metabolism. NetG1+ CAFs were intrinsically immunosuppressive and inhibited NK cell mediated killing of tumor cells. These pro-tumor functions were controlled by a signaling circuit downstream to NetG1, which was comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally blocking NetG1 with a neutralizing antibody stunted in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC.

中文翻译：

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Netrin G1通过癌症相关的成纤维细胞驱动的营养支持和免疫抑制作用促进胰腺肿瘤发生

胰腺导管腺癌（PDAC）的5年生存率很低，并且缺乏有效的治疗方法。因此，确定新目标至关重要。使用来自患者组织，三维共培养体外测定法和原位鼠模型的多重数据，我们确定了Netrin G1（NetG1）是PDAC肿瘤发生的促进剂。NetG1 +癌症相关的成纤维细胞（CAF）通过NetG1对谷氨酸/谷氨酰胺代谢的介导作用，支持PDAC的存活。NetG1 + CAF具有内在的免疫抑制作用，并抑制NK细胞介导的肿瘤细胞杀伤。这些促肿瘤功能由NetG1下游的信号转导电路控制，该信号转导电路由AKT / 4E-BP1，p38 / FRA1，囊泡谷氨酸转运蛋白1和谷氨酰胺合成酶组成。