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Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer
Cell ( IF 45.5 ) Pub Date : 2020-11-02 , DOI: 10.1016/j.cell.2020.10.016
Robert S Banh 1 , Douglas E Biancur 1 , Keisuke Yamamoto 1 , Albert S W Sohn 1 , Beth Walters 2 , Miljan Kuljanin 3 , Ajami Gikandi 3 , Huamin Wang 4 , Joseph D Mancias 3 , Robert J Schneider 5 , Michael E Pacold 1 , Alec C Kimmelman 1
Affiliation  

Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.



中文翻译:

神经元释放丝氨酸以支持胰腺癌中的 mRNA 翻译

胰腺导管腺癌 (PDAC) 肿瘤具有营养贫乏、促纤维增生和高度神经支配的肿瘤微环境。尽管神经元可以释放刺激因子以加速 PDAC 肿瘤发生,但尚未探索外周轴突的代谢贡献。我们发现外周轴突释放丝氨酸 (Ser) 以支持外源性 Ser (exSer) 依赖性 PDAC 细胞在 Ser/Gly(甘氨酸)剥夺期间的生长。Ser 剥夺导致核糖体在六个 Ser 密码子 TCC 和 TCT 中的两个上停滞,并允许 PDAC 细胞选择性翻译和分泌神经生长因子 (NGF) 以促进肿瘤神经支配。与此一致,exSer 依赖性 PDAC 肿瘤在无 Ser/Gly 饮食的小鼠中生长较慢并显示出增强的神经支配。使用 LOXO-101 阻断代偿性神经元神经支配,Trk-NGF 抑制剂,进一步降低了 PDAC 肿瘤的生长。我们的数据表明,轴突-癌症代谢串扰是支持 PDAC 在营养贫乏环境中生长的关键适应性。

更新日期:2020-11-26
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