ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma

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. [Display omitted] •Loss of p62 in the stroma reprograms metabolism to endure glutamine deprivation•Stromal loss of p62 upregulates ATF4 to sustain asparagine-mediated tumor growth•p62 regulates ATF4 stability through ubiquitin-mediated proteasomal degradation•Fibroblast-selective deletion of p62 activates the ATF4-ASNS axis in vivo Tumors suffer nutrient stress and need to reprogram their metabolism to survive. Linares et al. elucidate a key role for p62 in rewiring the metabolism of tumor stromal fibroblasts to sustain growth of both stromal and epithelial tumor cells, thus making p62 a novel cancer vulnerability point.