Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast-Driven Nutritional Support and Immunosuppression.
Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast-Driven Nutritional Support and Immunosuppression.
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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来促进胰腺肿瘤发生。
DOI：
10.1158/2159-8290.cd-20-0775
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发表时间：
2021-03
期刊：
影响因子：
28.2
通讯作者：
Cukierman E
中科院分区：
文献类型：
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作者：
Francescone R;Barbosa Vendramini-Costa D;Franco-Barraza J;Wagner J;Muir A;Lau AN;Gabitova L;Pazina T;Gupta S;Luong T;Rollins D;Malik R;Thapa RJ;Restifo D;Zhou Y;Cai KQ;Hensley HH;Tan Y;Kruger WD;Devarajan K;Balachandran S;Klein-Szanto AJ;Wang H;El-Deiry WS;Vander Heiden MG;Peri S;Campbell KS;Astsaturov I;Cukierman E
胰腺导管腺癌（PDAC）5年生存率低，缺乏有效的治疗方法。因此，确定新的目标至关重要。使用来自患者组织、三维共培养体外测定和原位小鼠模型的多重数据，我们将Netrin G1（NetG 1）鉴定为PDAC肿瘤发生的启动子。我们发现NetG 1+癌症相关成纤维细胞（CAF）通过NetG 1介导的谷氨酸/谷氨酰胺代谢作用支持PDAC存活。此外，NetG 1 + CAF本质上是免疫抑制性的，并抑制NK细胞介导的肿瘤细胞杀伤。这些促肿瘤功能由NetG 1下游的信号传导回路控制，NetG 1由AKT/4 E-BP 1、p38/FRA 1、囊泡谷氨酸转运蛋白1和谷氨酰胺合成酶组成。最后，用中和抗体阻断NetG 1阻碍体内肿瘤发生，表明NetG 1是PDAC的潜在靶点。
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. We found that NetG1+ cancer-associated fibroblasts (CAFs) support PDAC survival, through a NetG1 mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosuppressive and inhibit NK cell mediated killing of tumor cells. These pro-tumor functions are controlled by a signaling circuit downstream to NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC.