Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
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DOI：
10.1158/2159-8290.cd-19-1228
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发表时间：
2020-09-01
期刊：
影响因子：
28.2
通讯作者：
Pacold, Michael E.
中科院分区：
文献类型：
--
作者：
Ngo, Bryan;Kim, Eugenie;Pacold, Michael E.
转移的一个标志是肿瘤细胞对新环境的适应。丝氨酸和甘氨酸限制的脑环境所施加的代谢限制限制了转移性肿瘤的生长。人们对脑转移如何克服这些生长抑制条件知之甚少。在这里，我们证明3-磷酸甘油酸脱氢酶（PHGDH）催化葡萄糖衍生丝氨酸合成的限速步骤，是多种人类癌症类型和临床前模型中脑转移的主要决定因素。事实证明，增强的丝氨酸合成对于高度侵袭性脑转移细胞中的核苷酸产生和细胞增殖非常重要。在体内，PHGDH 的基因抑制和药物抑制减弱了脑转移，但没有减弱颅外肿瘤的生长，并提高了小鼠的总体生存率。这些结果表明，细胞外氨基酸的可用性决定了丝氨酸合成途径的依赖性，并表明 PHGDH 抑制剂可能有助于治疗脑转移瘤。 意义：利用蛋白质组学、代谢组学和多种脑转移模型，我们证明大脑的营养有限环境增强了脑转移瘤对丝氨酸合成抑制的敏感性。这些发现强调了在生理相关背景下研究癌症代谢的重要性，并为使用 PHGDH 抑制剂治疗脑转移提供了理论依据。
A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis.SIGNIFICANCE: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.