Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the direct control of ATF4 stability through its p62-mediated polyubiquitination. ATF4 upregulation by p62 deficiency in the stroma activates glucose carbon flux through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine generation as a source of nitrogen for stroma and tumor epithelial proliferation. Thus, p62 directly targets nuclear transcription factors to control metabolic reprogramming in the microenvironment and repress tumorigenesis, and identifies ATF4 as a synthetic vulnerability in p62-deficient tumor stroma.

中文翻译：

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ATF4诱导的代谢重编程是p62缺陷型肿瘤基质的综合脆弱性。

肿瘤经历营养应激，需要重新编程其代谢才能生存。通过提供营养以支持肿瘤的上皮区隔，基质在该过程中可能起关键作用。在这里，我们表明基质成纤维细胞中的p62缺乏症通过其p62介导的多聚泛素化直接控制ATF4稳定性，从而促进了对谷氨酰胺剥夺的抵抗力。基质中p62缺乏引起的ATF4上调通过丙酮酸羧化酶-天冬酰胺合成酶级联反应激活葡萄糖碳通量，从而导致天冬酰胺生成为基质和肿瘤上皮增殖的氮源。因此，p62直接靶向核转录因子，以控制微环境中的代谢重编程并抑制肿瘤发生，