Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer.
Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer.
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DOI：
10.1016/j.cell.2020.10.016
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发表时间：
2020-11-25
期刊：
影响因子：
64.5
通讯作者：
Kimmelman AC
中科院分区：
文献类型：
--
作者：
Banh RS;Biancur DE;Yamamoto K;Sohn ASW;Walters B;Kuljanin M;Gikandi A;Wang H;Mancias JD;Schneider RJ;Pacold ME;Kimmelman AC
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。虽然，神经元可以释放刺激因子，以加速PDAC肿瘤的发生，外周轴突的代谢贡献还没有被探索。我们发现，外周轴突释放丝氨酸（Ser），以支持生长的外源性Ser（exSer）依赖的PDAC细胞在Ser/Gly（甘氨酸）剥夺。丝氨酸剥夺导致核糖体在六个丝氨酸密码子中的两个上停滞，TCC和TCT，并允许PDAC细胞选择性地翻译和分泌神经生长因子（NGF）以促进肿瘤神经支配。与此相一致，exSer依赖性PDAC肿瘤生长较慢，并在无Ser/Gly饮食的小鼠中显示出增强的神经支配。使用LOXO-101（一种Trk-NGF抑制剂）阻断代偿性神经元神经支配进一步降低了PDAC肿瘤生长。我们的数据表明，轴突癌代谢串扰是一个关键的适应，以支持PDAC生长在营养不良的环境。在胰腺导管腺癌肿瘤中观察到的高水平神经支配提供丝氨酸，并且丝氨酸剥夺条件促进肿瘤神经支配以支持营养不良环境中的生长。
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. The high level of innervation seen in pancreatic ductal adenocarcinoma tumors supplies serine and serine-deprived conditions promote tumor innervation to support growth in nutrient poor environments.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
82.9
作者：
Davidson SM;Jonas O;Keibler MA;Hou HW;Luengo A;Mayers JR;Wyckoff J;Del Rosario AM;Whitman M;Chin CR;Condon KJ;Lammers A;Kellersberger KA;Stall BK;Stephanopoulos G;Bar-Sagi D;Han J;Rabinowitz JD;Cima MJ;Langer R;Vander Heiden MG
通讯作者：
Vander Heiden MG
DOI：
10.1073/pnas.200364497
发表时间：
2000-10-10
影响因子：
11.1
作者：
Furuya, S;Tabata, T;Hirabayashi, Y
通讯作者：
Hirabayashi, Y
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
3.3
作者：
Caroleo, MC;Costa, N;Aloe, L
通讯作者：
Aloe, L