Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer
Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer
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DOI：
10.1084/jem.20200388
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发表时间：
2020-09-01
影响因子：
15.3
通讯作者：
Commisso, Cosimo
中科院分区：
文献类型：
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作者：
Recouvreux, Maria Victoria;Moldenhauer, Matthew R.;Commisso, Cosimo
肿瘤细胞依赖谷氨酰胺来满足其代谢需求并维持增殖。谷氨酰胺消耗量增加可导致肿瘤内营养耗尽，引起代谢应激，可能影响肿瘤进展。在这里，我们表明，谷氨酰胺剥夺引起的营养应激导致胰腺导管腺癌（PDAC）细胞上皮间质转化（EMT）的诱导。从机制上讲，我们证明谷氨酰胺缺乏通过上调EMT主调节器Slug来调节EMT，这是一个依赖于MEK/ERK信号传导和ATF 4的过程。我们发现Slug是PDAC细胞中谷氨酰胺剥夺诱导的EMT，细胞运动和营养应激生存所必需的。重要的是，我们破译了Slug与PDAC肿瘤中的营养应激相关，并且是转移所必需的。这些结果描绘了鼻涕虫在营养应激反应中的新作用，并提供了对营养消耗如何影响PDAC进展的见解。
Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the up-regulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation-induced EMT, cell motility, and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.